full paper - RosDok - Universität Rostock

Leibniz–Institut für Katalyse e.V. an der Universität Rostock 

New Aspects in Homogeneous Hydrogenation – 

Development of Practical Rhodium Phosphine Catalysts 

and Environmentally Benign Iron Catalysts 

Dissertation 

zur Erlangung des akademischen Grades eines 

Doktor rerum naturalium (Dr. rer. nat.) 

vorgelegt der 

Mathematisch–Naturwissenschaftlichen Fakultät der Universität Rostock 

von 

Stephan Enthaler 

geb. am 27.02.1980 

Rostock, Mai 2007

Die vorliegende Arbeit entstand in der Zeit von September 2004 bis April 2007 am Leibniz– 

Institut für Katalyse e.V. an der Universität Rostock. 

Vollständiger Abdruck der von der Mathematisch–Naturwissenschaftlichen Fakultät der 

Universität Rostock zur Erlangung des akademischen Grades eines Doktors der 

Naturwissenschaft genehmigten Dissertation. 

Gutachter der Dissertation: Prof. Dr. Matthias Beller, Leibniz–Institut für 

Katalyse e.V. an der Universität Rostock 

(Erstgutachten) 

Prof. Dr. Serafino Gladiali, Dipartimento di 

Chimica, Universita` di Sassari, Sassari, Italien 

(Zweitgutachten) 

Prof. Dr. Uwe Rosenthal, Leibniz–Institut für 

Katalyse e.V. an der Universität Rostock 

(Drittgutachten) 

Termin des Rigorosums: 05. November 2007 

Prüfungsvorsitzender: Prof. Dr. Eckhard Vogel, Universität Rostock 

Prüfer Hauptfach (Organische Chemie): Prof. Dr. Matthias Beller, Leibniz–Institut für 

Katalyse e. V. an der Universität Rostock 

Prüferin Nebenfach (Toxikologie): PD Dr. Birgit Tiefenbach, Universität Rostock 

Wissenschaftliches Kolloquium: 15. Januar 2008

Ändere die Welt; sie braucht es. 

Bertolt Brecht (1898-1956)

Ich danke herzlich meinem hochgeschätzten Lehrer 

Prof. Dr. Matthias Beller 

für die Aufnahme in seine Arbeitsgruppe, die ausgezeichneten Arbeitsbedingungen, seinen 

unerschöpflichen Ideenreichtum und sein großes Interesse am Gelingen dieser Arbeit, sowie 

die gewährte wissenschaftliche Freiheit und sein Vertrauen.

Weiterhin gilt mein besonderer Dank den Mitgliedern der explorativen Projektgruppe 

„Synthese von neuen chiralen Liganden“ die einen maßgeblichen Anteil am Gelingen dieser 

Arbeit hatte: Meiner Themenleiterin Frau Dr. Kathrin Junge für die ausgezeichnete und 

freundschaftliche Zusammenarbeit und die gewährten Freiheiten während der letzten Jahre, 

Dipl.–Chem. Giulia Erre für ihre Freundschaft, Zusammenarbeit, den unzähligen Korrekturen 

und der kritischen Durchsicht dieser Arbeit (molte grazie!), ferner Dr. Bernhard Hagemann 

für seine Freundschaft und die vielen „wissenschaftlichen“ Diskussionen. 

Ferner gilt mein Dank Monika Heyken, Caroline Voss und Christine Mewes für die 

Durchführung ungezählter Experimente. 

Allen Freunden und Kollegen danke ich für ihre Unterstützung, Diskussionen, Chemikalien 

und die hervorragende Arbeitsatmosphäre: Dr. Sandra Hübner, Dipl. Chem. Kristin Schröder, 

Dipl.–Chem. Björn „Hartmut“ Loges, Dipl.–Chem. Hanns Martin Kaiser, Dipl.–Chem. 

Bianca Bitterlich, Dr. Kristin Mertins, Dipl.–Chem. Jan Schumacher, Dr. Jette Kischel, 

Dipl.–Chem. Cathleen Buch, Dr. Andrea „Lingelchen“ Christiansen, , Dr. Dirk Strübing, 

Dipl.–Chem. Anne Grotevendt, Dipl.–Chem. Anne Brennführer, Dipl.–Chem. Nicolle 

Schwarz, Dipl.–Chem. Karolin Alex, Karin Buchholz, Sandra Giertz, Dipl.–Chem. Benjamin 

Schäffner, Dipl.–Chem. Christian Torborg, Dipl.–Chem. Stefan Schulz, Dr.. Stefan Klaus, 

Dipl.–Chem. Thomas „Bob“ Schmidt, Dr. Marko Hapke, Dr. Ralf Jackstell, Dr. Henrik 

Junge, Dr. Helfried Neumann, Dr. Alexander Zapf, Dr. Hajun Jiao, Dr. Irina Jovel, Dr. 

Thomas Schareina, Dr. Holger Klein, Dr. Alexey Sergeev, Dr. Nicolas Clement, Chem. Ing. 

Christa Fuhrmann, Dr. Jens Holz, Dr. Annegret Tillack und vielen mehr. 

Herrn Dr. Man–Kin Tse danke ich für unzählige Diskussionen und den unerschöpflichen 

Vorrat an neuen Liganden. 

Prof. Dr. Serafino Gladiali für die vielen Diskussionen und die Zusammenarbeit. 

Dr. Torsten Dwars für die unzähligen Diskussionen und die unkomplizierte 

Chemikalienbeschaffung. 

Dem Analytik Team des Leibniz–Instituts für Katalyse: Dr. Dirk Michalik, Dr. Christine 

Fischer, Dr. Anke Spanneberg, Dr. Wolgang Baumann, Susanne Schareina, Karin Buchholz,

Kathleen Mevius, Astrid Lehmann, Kathrin Reincke, Christine Domke und im Besonderen 

Susann Buchholz für die Messung unzähliger GC–Proben. 

Der Degussa Homogeneous Catalysis (DHC) für die freundliche Bereitstellung 

verschiedenster Liganden. 

Mein ganz besonderer Dank gebührt meinen Eltern für ihre Unterstützung.

Table of Contents 

1. Introduction 

Page 

1 

2. Phosphorous containing ligands in the field of asymmetric 

hydrogenation 

3 

2.1. Monodentate phosphine ligands in rhodium–catalyzed asymmetric 

hydrogenation reactions of C–C double bonds 

4 

2.2. Monodentate ligands based on 4,5–dihydro–3H–dinaphtho[2,1–c;1´,2´– 

e]phosphepine motif in asymmetric hydrogenations of C–C double 

bonds 

17 

2.2.1. Monodentate ligands based on 4,5–dihydro–3H-dinaphtho[2,1–c;1´,2´– 

e]phosphepine scaffold in asymmetric synthesis 

29 

2.3. Concluding remarks 30 

2.4. References 31 

3. Reduction of unsaturated compounds with homogeneous iron 

catalysts 

39 

3.1. Introduction 40 

3.2. Hydrogenation of carbonyl compounds 41 

3.3. Hydrogenation of Carbon–Carbon Double Bounds 47 

3.4. Hydrogenation of imines and imino–analogues compounds 55 

3.5. Hydrosilylation 56 

3.6. Concluding Remarks 63 


4. Objectives of the work 65 

4.1. Application of monodentate phosphine ligands in asymmetric 

hydrogenation 

65 

4.1.1. Asymmetric hydrogenation of N–acyl enamides 65 

4.1.2. Asymmetric hydrogenation of β–dehydroamino acid derivates 65 

4.1.3. Asymmetric hydrogenation of enol carbamates 66 

4.2. Transfer hydrogenation 66 

4.2.1. Homogeneous iron catalyst in reduction chemistry 66 

4.2.2. Transfer hydrogenation of ketones with ruthenium catalysts 67

4.2.2.1. Transfer hydrogenation with ruthenium carbene catalysts 67 

4.2.2.2. Asymmetric transfer hydrogenation with ruthenium catalysts 67 


5. Application of monodentate phosphine ligands in asymmetric 

hydrogenation 

5.1. Enantioselective rhodium–catalyzed hydrogenation of enamides in the 

presence of chiral monodentate phosphines 

5.2. Development of practical rhodium phosphine catalysts for the 

hydrogenation of β–dehydroamino acid derivates 

5.3. Enantioselective rhodium–catalyzed hydrogenation of enol carbamates 

in the presence of monodentate phosphines 

87 

6. Transfer hydrogenation 100 

6.1. Homogeneous iron catalyst in reduction chemistry 100 

6.1.1. An environmentally benign process for the hydrogenation of ketones 

with homogeneous iron catalysts 

101 

6.1.2. Biomimetic transfer hydrogenation of ketones with iron porphyrin 108 

catalysts 

6.1.3. Biomimetic transfer hydrogenation of 2–alkoxy– and 2–aryloxyketones 

with iron porphyrin catalysts 

118 

6.2. Transfer hydrogenation of prochiral ketones with ruthenium 

catalysts 

125 

6.2.1. Efficient transfer hydrogenation of ketones in the presence of ruthenium 

N–heterocyclic carbene catalysts 

131 

6.2.2. New ruthenium catalysts for asymmetric transfer hydrogenation of 

prochiral ketones 

140 

7. Summary 143 

7.1. Application of monodentate phosphines in asymmetric hydrogenations 143 

7.2. Transfer hydrogenation 144 

69 

69 

76

Abbreviations 

Ac Acetyl 

Acac Acetylacetonate 

Anisyl Methoxylphenyl group 

Ar Aryl 

BICHEP 2,2´–bis(diphenylphosphino)–6,6´–dimethoxy–1,1´–biphenyl 

BINAP 2,2´–Bis(diphenylphosphino)–1,1´–binaphthyl 

Binaphane 1,2–Bis[4,5–dihydro–3H–binaphtho[1,2–c:2´,1´–e]phosphepino]benzene 

f-Binaphane 1,1´–Bis{4,5–dihydro–3H-dinaphtho[1,2–c: 2´,1´– 

e]phosphepino}ferrocene 

Binapine 4,4´–Di–tert–butyl–4,4´,5,5´–tetrahydro–3,3´–bis-3H–dinaphtho[2,1– 

c:1´,2´–e]phosphepine 

BINEPINE 4,5–Dihydro–3H–dinaphtho[2,1–c;1´,2´–e]phosphepine 

BINOL 2,2´–Binaphthol 

Bipy-tb Bis–tert–butyl–bipyridine 

Bn Benzyl 

BMPP Benzyl methyl phenyl phosphine 

Bopa-ip Bis(2–((S)–4–iso–propyl–4,5–dihydrooxazol–2–yl)phenyl)amine 

Bopa-tb Bis(2–((S)–4–tert–butyl–4,5–dihydrooxazol–2–yl)phenyl)amine 

BPE 1,2-Bis(2,5–diethylphospholano)ethane 

BPPM Butoxycarbonyl–4–diphenylphosphino–2–diphenylphosphinomethyl– 

pyrrolidine 

t–Bu tert–Butyl 

i–Bu iso–Butyl 

Bz Benzoyl 

CAMP Cyclohexyl o–anisylmethylphosphine 

Cat. Catalyst 

ChiraPhos Bis(diphenylphosphino)butane 

cod 1,5–Cyclooctadiene 

coe Cyclooctene 

Conv. Conversion 

Cp Cyclopentadienyl 

Cp´ Substituted cyclopentadienyl 

Cy Cyclohexyl 

DABCO 1,4–Diazabicyclo[2.2.2]octane 

DeguPhos Bis(diphenyl-phosphino)–1–benzyl–pyrrolidine 

DIOP O-Isopropyliden–2,3–dihydroxy–1,4–bis(diphenylphosphino)butane 

L–DOPA 3,4–Dihydroxyphenylalanine 

DIPAMP 1,2–Bis[(2–methoxyphenyl)(phenyl)phosphino]ethane 

DMSO Dimethylsulfoxide 

DPPE 1,2-Bis(diphenylphosphino)ethane 

DuPhos Bis(2,5–dimethylphospholano)benzene 

ee Enantiomeric excess 

e.g. Exempli gratia 

equiv. Equivalent 

Et Ethyl 

et al. et alii, et aliae or et alia 

gem Geminal 

h Hour 

JosiPhos 1–[2–(Diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine

L Ligand 

MandyPhos 2,2´-Bis[(N,N-dimethylamino)(phenyl)methyl]–1,1´– 

bisdicyclohexylphosphino)ferrocene 

Me Methyl 

Ment Menthyl 

MeOH Methanol 

MonoPhos 3,5–Dioxa–4–phosphacyclohepta[2,1–a;3,4–a´]dinapthalen–4– 

yl)dimethylamine 

MPPP Methyl phenyl n–propyl phosphine 

nbd Norbornadiene 

NMDPP Neomenthyldiphenylphosphine 

NorPhos 2,3–Bis(diphenylphosphino)–bicyclo[2.2.1]hept–5–ene 

OAc Acetate 

OMe Methoxy 

o Ortho 

PAMP Phenyl o–anisylmethylphosphine 

Ph Phenyl 

i–Pr i–Propyl 

n–Pr n–Propyl 

2-PrOH 2–Propanol 

Pybox 2,6–Bisoxazolin–2–yl pyridine 

R Organic rest 

r.t. Room temperature 

SDS Sodium dodecylsulfonate 

SiPhos 10,11,12,13–Tetrahydrodiindeno[7,1–de:1´,7´–fg][1,3,2]dioxaphosphocin– 

5–dimethylaniline 

Terpy 2,2´:6´,2´´–Terpyridine 

THF Tetrahydrofuran 

tmeda N,N,N´,N´–Tetramethylethylendiamine 

TMS Trimethylsilyl 

TOF Turnover frequency 

TON Turnover number 

X Halide

1. Introduction 1 


The importance of chiral compounds is demonstrated by their auspicious widespread 

applications as building blocks or intermediates for the synthesis of pharmaceuticals, 

agrochemicals, polymers, natural compounds, auxiliaries, ligands and synthons in organic 

syntheses. 1 To serve the growing demand of enantiomerically pure products various synthetic 

approaches were developed. Within the diverse consumers of chiral compounds the 

pharmaceutical industry provides one of the main impulses for new products, since nowadays 

only drugs containing single enantiomers are allowed to sign up for market. 2 This 

requirement was initiated as a consequence of different pharmacological studies, which 

affirmed different behaviour of both enantiomers, and proven by accidents with racemic 

drugs. 3 Hence, the development of new and improved methods for the preparation of 

enantiomerically pure compounds is an important target of industrial and academic research. 

Several synthetic approaches to optically active compounds have been realized in the past. 

Still one of the most practical approach is the separation of enantiomers via resolution, e.g. in 

the presence of chiral acids or enzymatic processes. The main drawback of this concept is the 

poor atom efficiency and the negative environmental impact, albeit nowadays promising 

efforts on dynamic kinetic resolutions have been established. 4 A more attractive access is 

represented by applying enantiopure materials from the “chiral pool”. Another powerful 

strategy is the application of stereoselective syntheses in particular reactions catalyzed by 

transition metal complexes, biocatalysts, and in recent years by organocatalysts. 1e-g,5 Within 

the different molecular transformations to chiral compounds transition metal catalyzed 

reactions offer an efficient and versatile strategy and presents a key technology for the 

advancement of “green chemistry”, specifically for waste prevention, reducing energy 

consumption, achieving high atom efficiency and generating advantageous economics. 6 Since 

the mid of the last century manifold catalytic reactions have been reported, e.g. 

polymerization, metathesis, cross couplings, hydroformylations, aminations or epoxidations. 1g 

One of the most popular and extensive studied catalytic reaction with respect to industrial 

applications is the asymmetric hydrogenation of unsaturated compounds containing C=C, 

C=O and C=N bonds since addition of molecular hydrogen provides high atom efficiency and 

the starting material are often readily available. 7 In this regard, for activation of the molecular 

hydrogen or hydrogen donors and transfer of chiral information the use of transition metal 

catalysts containing chiral ligands is essential. Commonly, chiral phosphorous ligands were 

used as source of chirality since catalysts including phosphorous systems proved to be highly

1. Introduction 2 

active as well as enantioselective. Furthermore diverse representatives are available on large 

scale. 8 The relevance of hydrogenation processes are impressively confirmed by several 

integrations in industrial applications (Scheme 1). 

HO 

OH 

NH 2 

L-DOPA 

anti Parkinson´s disease 

(Monsanto, 

VEB Isis-Chemie) 

via C=C hydrogenation 

OHC 

OH HN O 

NH 

COOH 

OH 

1 2 

COOMe 

3 4 

O 

Et 

O 

NH t Bu 

Crixivan 

HIV protease inhibitor 

(Merck, Lonza) 


(-)-Menthol 

building block for e.g. 

pharmaceuticals, 

flavours or cosmetics 

(Takasago) 

via isomerization and 

C=C hydrogenation 

Ph 

precursor for 

penem antibiotics 

(Takasago) 

via C=O hydrogenation 

and 

dynamic kinetic resolution 

Citronellol 

fragrance, vitamine E precursor 

(Takasago) 


MeO 

S-Metolachlor 

herbizide 

(Ciba-Geigy-Syngenta-Solvias) 

via C=N hydrogenation 

OH HCl 

OH 

N 

Bn 

HO 

5 6 OH 

7 

Adrenaline 

β-adrenergic receptor activator 

(Boehringer-Ingelheim) 


Scheme 1. Selection of industrial important compounds synthesized via hydrogenation protocols in 

the presence of chiral catalysts containing chiral phosphines. 9 

However, the generality of asymmetric hydrogenation is deeply limited by the substrate- 

structure and transferability of method since no universal catalyst is on hand, which shows 

extraordinary behaviour for most classes of substrates. Hence the discovery of new effective 

ligands is an important challenge for industrial and academic research. 7,10 Furthermore the 

final breakthrough in industry is hampered by catalysts containing expensive and toxic late 

transition metals (Ir, Rh or Ru). Therefore, substitution by ubiquitous available, inexpensive 

and less toxic metals is one of the challenging objectives for future research. In this regard the 

use of iron catalysts is especially desirable. 11

2. Phosphorous containing ligands in the field of asymmetric hydrogenation 


“The inherent generality of this method offers almost unlimited opportunities for matching 

substrates with catalysts in a rational manner and we are hopeful that our current effort will 

result in real progress towards complete stereospecificity.” W. S. Knowles and M. J. Sabacky 12 

Since the pioneering investigations on asymmetric hydrogenation by Knowles, Kagan, and 

others in the late 1960s of the last century extensive efforts were undertaken to develop this 

powerful method. In the early stage of investigations phosphorous ligands have been proven 

to be beneficial by supporting the catalyst activity and transferring the chiral information. A 

huge number of successful ligand concepts have been developed during the last decades. 

Nowadays they are most frequently used in the field of asymmetric C=C bond 

hydrogenations. However, even if several industrial applications on small to medium scale are 

established the final breakthrough is so far not reached, due to the low transferability of 

technique to novel demands. Therefore, tailor–made catalysts designed for well–defined tasks 

are important tools for achieving high activity and enantioselectivity. Based on this fact the 

discovery of new effective ligands is a key challenge for industrial and academic research. 

Innovative catalysts must fulfil several requirements for successful industrial applications. On 

the one hand an easy to adopt synthetic approach on large scale and straightforward structural 

variation of the ligand key structure must be available (ligand library). Furthermore, the 

catalyst must attain reasonable activity and enantioselectivity in the investigated reaction. On 

the other hand intellectual property should be accessible. 13 

In this regard, the development of new ligands for asymmetric hydrogenation has focused on 

the synthesis of bidentate ligands for nearly 30 years. However, at the end of the 20 th century 

the predominant role of bidentate ligands changed and monodentate ligands received more 

attention. 14,15 The advantages of monodentate phosphorous ligands are their easier synthesis 

and tunability compared to bidentate counterparts. The capabilities of monodentate ligands 

were successful demonstrated in several reactions. 16 Nowadays monodentate ligands are 

accepted as additional tool in asymmetric hydrogenations. 

This review will focus on the application of monodentate phosphine ligands in asymmetric 

hydrogenations of C–C double bonds. 

3


2.1. Monodentate phosphine ligands in rhodium–catalyzed asymmetric hydrogenation 

reactions of C–C double bonds 

“The considerable variation of yields with phosphine structure clearly shows the need for a 

match of catalyst and substrate.” W. S. Knowles, M. J. Sabacky, and B. D. Vineyard 17 

The beginning of homogenous hydrogenation started in the mid of the sixties of the last 

century and is connected with the groups of Wilkinson and Vaska. Thereby the group of 

Wilkinson reported the first successful application of a well–defined complex [RhCl(PPh3)3] 

(Wilkinson´s catalyst) 18 in homogeneous hydrogenation of simple olefins with molecular 

hydrogen, while shortly after Vaska obtained similar results with Ir(CO)(PPh3)3 as catalyst 

(Vaska´s complex). 19 Based on this seminal work a first chiral version was independently 

presented by the groups of Knowles and Horner 20 in 1968 right after Mislow et al. 21 and 

Horner et al. 22 established an approach to P–chiral ligands via resolution of diastereomeric 

menthyl phosphinates and subsequent reaction with Grignard reagents and phosphine oxide 

reduction (Scheme 2). 

Horner and Mislow 

MentO 

Knowles and Sabacky 

Horner 

O 

MentO P R 1 

R 2 

COOH 

resolution 

O 

P R 1 

0.15 mol% RhCl 3(8a) 3 

3.5 mol% NEt 3, H 2 

COOH 

* 

benzene-ethanol (1:1), 60 °C 

9 10 

R 

R 2 

1. R 3 MgX 

2. HSiCl 3 

8a: R 1 = Ph, R 2 = Me, R 3 = i-Pr 

8b: R 1 = Ph, R 2 = Me, R 3 = n-Pr (MPPP) 

8c: R 1 = Ph, R 2 = Me, R 3 = Bn (BMPP) 

8d: R 1 = Ph, R 2 = Me, R 3 = o-Anisyl (PAMP) 

1/2 [Rh(cod)Cl] 2 / (8b) 

H 2 (1 atm) 

15% ee 

R 3 P R 1 

R 2 

benzene, r.t. 

11a-b 12a-b 

R 

* 

12a: R = Et: 7-8% ee 

12b: R = OMe: 3-4% ee 

Scheme 2. Synthetic approach to chiral monodentate phosphines and first asymmetric hydrogenations 

carried out with homogeneous catalyst. 

4


In the reduction of α–phenylacrylic acid 9 a promising enantiomeric excess of 15% was 

attained when using rhodium–complexes with ligands of type 8. Hereafter, various attempts, 

specially focused on modification of the ligand structure were carried out to improve the 

enantioselectivity but unfortunately no decisively enhancement was gained. 23 Parallel to this 

work Horner et al. applied an in situ catalyst composed of [Rh(cod)Cl]2 and 4 equiv. of 

optical active methylphenyl–n–propylphosphine 8b in the asymmetric hydrogenation of α– 

ethylstyrene 11a and α–methoxystyrene 11b, only low enantioselectivities (


to further improve the enantioselectivity in asymmetric hydrogenations. During the years 

various strategies for inducing the chirality were successfully demonstrated, for instance 

transfer of chirality by different sources, e.g. axial chirality or P–chirality. Furthermore, the 

bite angle model (phosphorous–metal–phosphorous angle) and the formed ring sizes of 

phosphorous–metal–phosphorous system displayed to be crucial. In Scheme 4 a selection of 

outstanding bidentate ligand systems is presented. Enantioselectivities greater then >99% ee 

for a tremendous number of substrates were reported. 

H 

O 

O 

H 

DIOP (13) 

(1971) 

BINAP (19) 

(1980) 

PPh2 PPh2 PPh2 PPh2 R PPh2 R PPh2 BIPHEP (23) 

(1988) 

Ph 2P 

Et 

PPh 2 

H 

PPh 2 

NorPhos (20) 

(1981) 

Et 

N 

O O 

BPPM (16) 

(1976) 

Fe 

PPh 2 

PPh 2 

PPh 2 

Et 

Et 

MandyPhos (24) 

(1989) 

Scheme 4. Selection of outstanding bidentate ligands. 25,27 

MeO 

P 

P 

OMe 

DIPAMP (17) 

(1977) 

Ph 2P PPh 2 

N 

DeguPhos (21) 

(1984) 

P P 

DuPhos (25) 

(1990) 

Ph 2P 

PPh 2 

Fe 

PPh 2 

ChiraPhos (18) 

(1977) 

JosiPhos (22) 

(1994) 

P P 

BPE (26) 

(1990) 

At the early stage of bidentate ligands, enantioselectivities up to 90% ee were obtained in the 

hydrogenation of phenyl alanine derivatives with monodentate CAMP ligand 29 by Knowles 

et al. by increasing the optical purity 28 of P–chiral ligands and the introduction of o–anisyl 

17, 23, 29 

group, which probably affords a hemilabile second coordination via methoxy–group. 

6 

PCy 2

MeO 

HO 

27 


O Ph 

NH 

COOH 

0.03 mol% [Rh(1,5-hexadiene)] 2 

0.06 mol% 29 

1 equiv. NaOH, H 2 (55 psi) 

2-PrOH, 50 °C 

MeO 

HO 

* 

90% ee 

O Ph 

NH 

COOH 

28 

7 

P Me 

OMe 

CAMP (29) 

Scheme 5. Asymmetric hydrogenation of α–dehydroamino acid derivatives to yield a L–DOPA 

precursor. 

Although this excellent enantioselectivities were gained, the displacement of monodentate 

ligands by bidentate systems could not be impeded and led to a resting state for approximately 

30 years (Scheme 6). Also the pioneers of this research area directed their efforts to bidentate 

ligands, e.g. Knowles and co–workers synthesized a dimeric version of the PAMP ligand 

(Scheme 2, 8d), so called DIPAMP 17 (Scheme 4) and achieved enantioselectivities up to 

96% ee. 30 

Monodentate 

Ligands 

Bidentate 

Ligands 

Knowles, 

Sabacky, Horner 

ligand 8 

Kagan, 

DIOP 

Knowles, 

CAMP 

1968 1971 1972 1977 1980 1993 1994 since 2000 

Knowles, 

DIPAMP 

Noyori, 

BINAP 

Scheme 6. Historical classification of developments in ligand synthesis. 

Burk, 

DuPhos 

Togni, 

JosiPhos 

Renaissance 

Albeit from time to time attempts were undertaken to refocus on monodentate systems the 

situation did not change significantly. For instance at the end of the 70 th the ligand concept 

presented in Scheme 2 was taken up again by Solodar for the asymmetric hydrogenation of 

challenging piperitenone 30, thereby monodentate ligands induced higher enantioselectivity 

than bidentate systems, even if the obtained enantiomeric excesses were comparatively low 

(up to 38% ee) (Scheme 7). 31 The influence of reaction conditions on enantioselectivity and 

chemoselectivity were studied in detail but no considerable improvements were attained. 

Noteworthy, the chemoselectivity is crucial for this type of substrate, because as side products 

pulegone (hydrogenation of the endocyclic double bond), menthones (hydrogenation of both


double bonds) and menthols (hydrogenation of both double bonds and the ketone 

functionality) were observed. 

O 

[Rh(cod)(29) 2]BF 4 

H 2 (120 psig) 

MeOH, 80 °C, 3 h 

* O 

30 31 

38% ee 

conv. 72%, selectivity: 45% 

Scheme 7. Synthesis of piperitone 31 via asymmetric hydrogenation. 

P Me 

OMe 

CAMP (29) 

Valentine et al. used a similar ligand concept as described by Morison and co–workers 24 for 

the reduction of ambitious compound 32 (Scheme 8), which resembles a precursor of α– 

tocopherol (vitamin E) or phylloquinone (vitamin K1). 32 As additional chiral carrier to the 

chiral menthyl–group a P–chirality was embedded and enantioselectivities up to 79% ee were 

attained with rhodium catalyst [Rh(cod)(34)2]BF4. Unfortunately, no information on the 

outcome of the reaction was given regarding the influence of ligand stereochemistry since 

matched and mismatched combinations are feasible. 

Me 

Ph P 

Me 

32 

N 

H 

COOH 

0.7 mol% [Rh(cod)(34) 2]BF4, H2 (2.75 atm) 

COOH 

34 

COOH 

NHAc 

NaOMe (1.1 equiv.), 

H 2 (2.75 atm), MeOH, r.t. 

79% ee (R), 

conv. >99%, TOF = 2.4 h -1 

0.1 mol% [Rh(cod)Cl] 2 0.2 mol% equiv. CAMP 

H 2 (2.75 atm) 

α-Tocopherol (35) 

COOH 

Me N 

36 MeOH, 23 °C, 36 h 

H 37 

Scheme 8. Asymmetric hydrogenations carried out by Valentine et al. 

67% ee 

conv. >99% 

Furthermore, α–dehydroamino acids precursors were hydrogenated in the presence of 

monodentate ligands, e.g. CAMP 29, in a comparative study with DIOP 13. The obtained 

33 

O 

NHAc 

8 

OH


results led to a marginal higher enantioselectivity for DIOP (72% ee) compared to CAMP 

(67% ee). 

In the mid of the 1980s Morita et al. developed an approach to sugar–based monodentate 

phosphines. 33 Initially started from readily available D–glucose a series of chemical 

transformations were carried out to attain ligand 38a. The catalytic potential was tested in the 

rhodium–catalyzed asymmetric hydrogenation of N–acetyl dehydrophenylalanine and the 

corresponding methyl ester (Scheme 9). Excellent enantioselectivity of 92% ee was obtained, 

albeit long reaction times were necessary. A competitive experiment performed with DIOP as 

ligand lead to somewhat lower enantioselectivity of 75% ee and demonstrated the 

extraordinary behaviour of monodentate ligand 38a under described conditions. The 

unfavourable long reaction times were overcome by increasing the initial hydrogen pressure, 

unfortunately accompanied by degradation of enantioselectivity. Furthermore, the influence 

of metal–ligand–ratio was studied. A significant effect on enantioselectivity as well as 

conversion was found when a ratio of 1:1 was used. The enantioselectivity decreased to 31% 

ee and a prolonged reaction time of one week was necessary to reach full conversion. Indeed, 

this result was approved by previous works by Knowles et al. concerning the necessity of 2 

equiv. ligands with respect to the metal, when a monodentate coordination mode is present. 

However, the catalytic behaviour of ligand 38b, synthesized by reduction of 38a, displayed a 

converse performance, since utilizing a metal–ligand–ratio of 1:1 a slight increase of 

enantioselectivity and a comparable conversion were observed. Interestingly, also the 

antipode enantiomer was detected. The authors assumed a bidentate coordination of the 

ligand, due to the attendance of the NH2–functionality and the construction of a six– 

membered ring. In addition, both systems were tested in the hydrogenation of itaconic acid 

derivatives; thereby ligand 38a exhibited once more an extraordinary enantioselectivity up to 

90% ee. 

H 

NC 

H 

O 

PPh 2 

O 

PPh2 NH2 O 

O 

O 

LiAlH 4 

O 

38a 

38b 

Ph 

NHAc 

COOR 

Scheme 9. Sugar–based monodentate ligands by Morita et al. 

2 mol% [Rh(cod) 2Cl] / 38 

H 2 (1 atm) 

benzene-methanol (1:4), r.t. 

Ph 

ligand: 38a (4 mol%) 

15b: R = H: 92% ee (S), conv. 84% (72 h) 

40: R = Me: 71% ee (S), conv. 51% (72 h) 

ligand: 38b (2 mol%) 

15b: R = H: 39% ee (R), conv. >99% (72 h) 

40: R = Me: 16% ee (R), conv. >99% (72 h) 

9 

* NHAc 

COOR 

14b, 39 15b, 40


Marinetti and co–workers focused on the synthesis of chiral phosphiranes, which are 

interesting ligands, because of their high s–character of the phosphorous lone pair, but 

unfortunately accompanied by high cyclic strain, which causes easy ring opening. 34 However, 

insertion of optical active phosphorous compounds into enantiopure styrene oxide yields 

molybdenum phosphirane complexes and subsequent transmetallation with rhodium 

complexes attained suitable precursors for asymmetric hydrogenation. The authors carried out 

a matched and mismatched study of all diasteriomeric combinations of ligand 41 in the 

hydrogenation of N–acetyl dehydrophenylalanine methyl ester 39 (Scheme 10). The best 

performance was shown by ligand 41b with an enantioselectivity of 76% ee, while all other 

combinations gained almost racemic mixtures. Marinetti et al. assume a better transfer of 

chirality, due to the cis–position of the phenyl group with respect to the metal, which causes 

steric interactions and in consequence a formation of a more stereospecific pocket. Changing 

the L–menthyl by t–butyl group (41e and 41f) confirmed the assumption, because trans– 

system led to higher enantioselectivity. 

Men 

P 

t-Bu 

P 

41a: P(S)C(S) (cis) 

41b: P(R)C(S) (trans) 

41c: P(R)C(R) (cis) 

41d: P(S)C(R) (trans) 

t-Bu 

P 

41e: cis 41f: trans 

Scheme 10. Phosphiranes as ligand in asymmetric hydrogenation. 

Ph 

NHAc 

Ph 

* 

COOMe 

NHAc 

1 mol% [Rh(cod)(41) 2]PF6 H2 (3.5 bar) 

methanol, 25 °C 

COOMe 

39 40 

41a: 9% ee (+) 

41b: 76% ee (-) 

41c: 3% ee (-) 

41d: 6% ee (+) 

41e: 26% ee (-) 

41f: 49% ee (-) 

Later the same group reported about an expansion of the ring size of the ligand. 35 The 

synthesis of chiral phosphetanes of type 42 (Scheme 11) was carried out according to the 

McBride approach, by reaction of branched olefins with chlorophosphine–AlCl3 complexes. 

The stereochemistry was regulated by chiral induction of L–menthyl as auxiliary. The acidic 

protons adjacent to the phosphorous atom enable further functionalization, for instance 

deprotonation with n–butyl lithium and subsequent quenching with benzyl bromide yields 

ligand 42. Ligand 42 was subjected to hydrogenation benchmark tests, but unfortunately the 

standard protocol, e.g. hydrogenation of N–acetyl dehydrophenylalanine with rhodium 

10


catalyst attained only low catalytic activity (8 days reaction time) and moderate enantiomeric 

excess of 40% ee. After switching to iridium as metal source, improved activity after 16 h was 

observed, but accompanied by lower enantioselectivity (


Pioneering work in the second age of monodentate ligands was presented in the late 90 th of 

the last century by the group of Fiaud applying a monodentate phospholane ligand (R,R)–45 

(Scheme 13), which resembles the structural motif of DuPhos 25. 37 Albeit the group of Burk 

demonstrated in one of their early articles the potential of ligand substituted with methyl 

groups (R,R)–44 in the hydrogenation of 39 (60% ee (R)) and dimethyl itaconate (65% ee (R)) 

with catalyst activities up to 500 h -1 , their research interest focused on the development of 

new chiral bisphosphines and 44 was mainly used as intermediate or building block. 38 

However, Fiaud obtained an enantioselectivity of 82% ee in the rhodium–catalyzed 

hydrogenation of N–acetyl dehydrophenylalanine methyl ester using an in situ catalyst 

composed of 1 mol% [RhCl(cod)]2 and 2.1 mol% corresponding ligand. 

P Ph Burk et al. 

Ph 

P 

Ph 

44 

Ph 

45 

Fiaud et al. 

Ph 

NHAc 

COOMe 

cat. / H 2 (atm.) 

MeOH, 20-25 °C 

Ph 

39 40 

Burk: 60% ee (R), TON = 1000, TOF = 333 h -1 

(0.01 mol% [Rh(cod)(44) 2]SbF 4) 

Fiaud: 82% ee (S) 

(in situ: 1 mol% [Rh(cod)Cl] 2, 2.1 mol% 45) 

Fiaud: 93% ee (S), t 1/2= 12 min 

(in situ: 1 mol% [Rh(cod) 2]BF 4, 2.1 mol% 45) 

* NHAc 

COOMe 

Scheme 13. Asymmetric hydrogenation of N–acetyl dehydrophenylalanine methyl ester with 

monodentate phospholanes. 

Later on the same group reported efforts on improving the enantioselectivity, by switching 

from [RhCl(cod)]2 as metal source to [Rh(cod)2]BF4 which resulted in a significant increase of 

enantiomeric excess to 93% ee. 39 Furthermore, the scope and limitation of ligand 45 was 

displayed by substrate variation, once dimethyl itaconate was hydrogenated in 55% optical 

yield, while for the corresponding acid a selectivity of 73% ee was attained. On the other hand 

N–acetyl enamides, for instance (Z)–N–(1–phenylprop–1–enyl)acetamide, were hydrogenated 

with good enantioselectivities up to 73% ee. In their ongoing research they became interested 

in stabilizing the air–sensitive phosphine by the phospholanium tetrafluoroborate counterpart 

and liberate the phosphine during the formation of the catalyst precursor. A slight decrease of 

enantioselectivity (86% ee (R)), accompanied by higher catalyst activities, was shown when 

applying this precursor in the hydrogenation of N–acetyl dehydrophenylalanine methyl ester 

with comparable reaction conditions as previous reported by them. 40 

12


At the end of the 20 th century the predominant role of bidentate ligands changed and 

monodentate ligands received more attention since first attempts by different groups have 

proven extraordinary transfer of chirality by applying monodentate phosphorous ligands 

41, , 

based on binaphthol in asymmetric hydrogenation. 42 43 The advantages of this type of 

monodentate phosphorous ligands are their easier synthesis and high tunability compared to 

bidentate phosphines, because designated target is accomplished in commonly 1–2 step 

synthesis starting from low cost chiral binaphthol. Scheme 14 illustrates some examples of 

monodentate phosphorous ligands for asymmetric hydrogenation based on the chiral 1,1´– 

binaphthol skeleton. Important contributions in this area came independently from Feringa 

and de Vries et al. 41 (phosphoramidites 46), Reetz et al. 42 (phosphites 47), and Pringle and 

Claver et al. 43 (phosphonites 48). Furthermore, excellent enantioselectivity was shown by 

Zhou and co–workers applying monodentate spiro phosphoramidites (SIPHOS, 49) 44 and 

many others. 45 The rediscovery of monodentate ligands was furthermore driven by conceptual 

review articles by Kagan and Börner, who assumed a better transfer of the chiral information 

due to the catalyst structure. Until now various systems based on the preliminary structure 

motif (46–48) have been proven to be highly active in diverse classes of asymmetric 

hydrogenations with enantioselectivities up to >99% ee and a few numbers of representatives 

have been commercialized. 

O 

P NR1R2 O 

O 

P OR 

O 

O 

P R 

O 

46 47 48 49 

Scheme 14. Selection of successful chiral monodentate ligands in asymmetric hydrogenations. 

13 

NR1R2 O P 

O 

However, during this time also some efforts on monodentate phosphines were reported. 

Marinetti and co–workers adopted the synthetic strategy of DuPhos–ligands, via formation of 

cyclic sulfates, for the synthesis of monodentate phosphetanes 50 (Scheme 15). 46 A huge 

number of potential ligands were accessible. Three ligands were chosen for testing their 

abilities in asymmetric hydrogenation of N–acetyl dehydrophenylalanine. In comparison to 

former achievements with phosphetanes an improved enantioselectivity up to 86% ee was 

monitored, albeit the i–propyl–derivative gave only low selectivity.

R 

P 

R 

50a: R = Me 

50b: R = i-Pr 

50c: R = Bn 


Scheme 15. Phosphetane ligands established by Marinetti et al. 

Ph 

NHAc 

1 mol% [Rh(cod)(50) 2]PF6 H2 (3-5 bar) 

Ph 

* NHAc 

COOH 

Methanol, r.t., over night 

COOH 

14a 15a 

50a: 80% ee, conv. >99% 

50b: 10% ee, conv. >99% 

50c: 86% ee, conv. >99% 

Afterwards Helmchen et al. exposed the extraordinary catalytic behaviour of 

oxaphosphinanes in asymmetric hydrogenation reactions (Scheme 16). 47 The ligands were 

synthesized by mesylation of enantiopure diolethers and subsequent reaction with 

dilithiophenylphosphine. Because of oxygen–sensitivity a stabilization with BH3 was 

appropriated. The oxaphosphinanes boranes were deprotected with DABCO (1,4– 

diazabicyclo[2.2.2]octane) before pre–catalyst formation was carried out. Preliminary 

experiments with ligand 51b pointed out moderate enantioselectivity of 47% ee for 

hydrogenation of N–acetyl dehydrophenylalanine. However, the authors assumed an 

unfavoured sterical shielding of the rhodium therefore the phenyl group was removed and 

substituted by hydrogen. Indeed, significant higher enantioselectivity (86% ee) and reaction 

rates were attained after re–starting the catalytic investigations with secondary phosphine 52b. 

This fact was further approved in the hydrogenation of itaconic acid 53, because 73% ee for 

51b and 93% ee for 52b, respectively, were achieved. Moreover, excellent enantioselectivity 

up to 96% ee was induced by variation of the α–position adjacent to the phosphorous atom. 

R P R 

Ph BH3 R 

O 

O 

P R 

H BH3 DABCO 

1. Li 

2. MeOH 

DABCO 

R 

51a: R = Me 

51b: R = i-Pr 

51c: R = Cy 

R 

O 

P 

Ph 

O 

P 

H 

R 

R 

52a: R = Me 

52b: R = i-Pr 

52c: R = Cy 

HOOC 

Ph 

NHAc 

COOH 

COOH 

Scheme 16. Oxaphosphinanes approached by Helmchen et al. 

53 

[Rh(cod)(L) 2]BF 4 / H 2 (1.1 bar) 

20 °C, 24 h 

14b 15b 

Ph 

ligand 51b: 47% ee (S) (1 mol% cat., MeOH) 

ligand 52b: 86% ee (S) (1 mol% cat., MeOH) 

ligand 52c: 90% ee (R) (1 mol% cat., CH 2Cl 2) 

[Rh(cod)(L) 2]BF 4 / H 2 (1.1 bar) 

20 °C, 24 h 

HOOC 

ligand 51b: 73% ee (R) (1 mol% cat., MeOH) 

ligand 52b: 93% ee (R) (0.2 mol% cat., 2-PrOH) 

ligand 52c: 96%ee (S) (0.2 mol% cat., 2-PrOH) 

14 

* NHAc 

COOH 

* COOH 

54


The group of Börner reported the synthesis and catalytic application of monodentate chiral 

phospholanes 55 (Scheme 17). 48 Two general synthetic sequences were envisaged. On the 

one hand, as key step a heterogeneous arene hydrogenation of dibenzophosphole acid was 

carried out, but unfortunately only a single product was isolated, while in total five 

diastereomers could be formed. The X–ray structure analysis indicated a cis–selective 

hydrogenation. Secondly, an improved McCormack reaction was performed to build up the 

basic ligand structure, and follow up chemistry yields ligand 55. Further on epimerization was 

investigated theoretically as well as practically to broaden the access to other diastereomers. 

As predicted by calculations the stereocenter adjacent to the phosphorous atom allows 

epimerization in the presence of base and subsequent acidification. Transformation of 

received acids to the corresponding secondary phosphines yields two diastereomers, which 

were separated via borane adduct. Unfortunately, deprotection of the single diastereomers led 

to epimerization of the P–chiral phosphorous atom. However, the mixture of diastereomers 

was tested in the hydrogenation of dimethyl itaconate and N–acetyl dehydrophenylalanine 

methyl ester, thereby moderate enantioselectivities were attained. 

P 

H 

P 

H 

55a 

55b 

55 

(mixture of epimers 

55a and 55b) 

MeOOC 

Ph 

COOMe 

MeOOC * 1 mol% [Rh(cod) 2]BF4 / 2 mol% 55 

H2 (1 bar) 

25 °C, 4 h 

COOMe 

56 

45% ee (R) (CH2Cl2) 52% ee (R) (MeOH) 

57 

NHAc 

COOMe 

1 mol% [Rh(cod) 2]BF 4 / 2 mol% 55 

H 2 (1 bar) 

25 °C, 4 h 

39 23% ee (S) (CH2Cl2) 40 

61% ee (S) (MeOH) 

Scheme 17. Secondary phosphine based on phospholane in asymmetric hydrogenation. 

Ph 

* NHAc 

COOMe 

More recently, Börner et al. reported a second type of monodentate phospholes, based on 

tartaric acid, which allows easy integration of chiral informations. 49 The key step was a 

double hydrophosphination. The obtained ligands were subjected to asymmetric 

hydrogenation of α– and β–dehydroamino acid derivates. Excellent enantioselectivity of 92% 

ee was attained for the hydrogenation of β–dehydroamino acid derivatives. 

15

O O 

O O 

P 

P 


58a 

O O 

O O 

58b 

R 1 

NHAc 

COOR 2 


H 2 (1 bar) 

r.t. 

ligand 58a: 

40: R1 = Ph, R2 = Me: 76% ee (S) (MeOH, 230 min) 

60: R1 = H, R2 39, 59 40, 60 

= Me: 81% ee (S) (CF3CH2OH, 17 min) 

NHAc 

COOR 3 

R 1 

ligand 58b: 

40: R 1 = Ph, R 2 = Me: 65% ee (S) (THF, 55 min) 

60: R 1 = H, R 2 = Me: 78% ee (S) (THF, 6 min) 


H 2 (1 bar) 

* NHAc 

COOR 2 

CF3CH2OH, r.t. 

ligand 58b: 

62a: R3 = Me: 82% ee (S) (200 min) 

62b: R3 61a-b 

= Bn: 92% ee (S) (180 min) 

62a-b 

Scheme 18. Monodentate phospholane ligands based on tartaric acid. 

16 

NHAc 

* COOR3 Breit et al. reported the synthesis of chiral phosphabarrelenes 62, which contain highly 

pyramidalized phosphorous atoms. 50 The ligands were accessible by Diels Alder reaction of 

substituted phosphabenzene and benzyne and subsequent separation of isomers. 

Unfortunately, testing these monodentate ligands in asymmetric hydrogenation protocols only 

moderate enantioselectivities were obtained in the hydrogenation of itaconic acids. However, 

improvement of enantioselectivity up to 90% ee was attained when the phosphabarrelene 62d 

was reacted with compound 48 (Scheme 14, R = Cl) to yield a bidentate ligand system. 

R 1 

P 

Ph 

R 2 

62a: R 1 = Ph, R 2 = 2-Napthyl 

62b: R 1 = Ph, R 2 = 3-MeO-C 6H 4 

62c: R 1 = Ph, R 2 = 2-MeO-C 6H 4 

62d: R 1 = Ph, R 2 = 2-HO-C 6H 4 

HOOC 

COOH 

1 mol% [Rh(cod) 2]BF4, 2.8 mol% 62 

H2 (1 bar) 

HOOC 

CH2Cl2, r.t. 

* COOH 

53 54 

Scheme 19. Chiral phophabarrelene in asymmetric hydrogenation. 

(+)-62a: 31% ee (R), conv. >99% (6 h) 

(-)-62a: 31% ee (S), conv. >99% (4 h)


2.2. Monodentate ligands based on 4,5–dihydro–3H–dinaphtho[2,1–c;1´,2´– 

e]phosphepine motif in asymmetric hydrogenations of C–C double bonds 

“We can expect that they (monophosphines) will play a role of increasing importance in many 

aspects of organometallic catalysis.” F. Lagasse and H. B. Kagan 

Ligands based on the 4,5–dihydro–3H–dinaphtho[2,1–c;1´,2´–e]phosphepine scaffold 66 are 

known since the early 90´s (Scheme 20) when Gladiali and co–workers reported the first 

successful synthesis of this ligand class. 51 The synthetic route is presented in Scheme 20. As 

initial step 2,2´–dimethylbinapthyl was synthesized via nickel–catalyzed Kumada coupling 

reaction of 1–bromo–1–methylnapthaline 63 and the corresponding Grignard reagent 64. 

63 

64 

Br 

+ 

CH 3 

MgBr 

CH 3 

P Ph 

66a 

NiCl 2(PPh 3) 2 

N Pd 

Cl 

Cl 

Pd 

N 

67 

CH3 CH3 + 

1. n-BuLi, KO t Bu, tmeda 

2. Cl 2PR 

N 

Cl 

Pd 

P Ph 

N 

Cl 

Pd 

P Ph 

Scheme 20. Approach to chiral phosphepines according to Gladiali et al. 

65 

68a 

68b 

DPPE 

DPPE 

66 

+ 

P R 

17 

P Ph 

(S)-66a 

P Ph 

(R)-66a 

The racemic 2,2´–dimethylbinapthyl 65 was selectively double–lithiated on the methyl groups 

and subsequent quenched with dichlorophosphines to yield the racemic 4,5–dihydro–3H–


dinaphtho[2,1–c;1´,2´–e]phosphepines 66. Resolution of the enantiomers was undertaken on 

racemic 66a and carried out by reacting the racemic mixture with (+)–di–μ−chloro-bis[(S)– 

N,N–dimethyl–α–phenylethylamine–2C,–N]-dipalladium 67 52 to form diastereomeric 

complexes 68a and 68b. The complexes were separated via crystallization. Finally, the 

enantiopure monodentate phosphine 66a (Ph–BINEPINE) was liberated by reacting the single 

diastereomeric complex with bidentate phosphines (e.g. DPPE). 

The potential of obtained enantiopure ligand (S)–66a was tested in asymmetric rhodium– 

catalyzed hydroformylation of styrene 69 under standard conditions (Scheme 21). Good 

iso/n–ratio of aldehyde (70:71) was found (95:5) and even if low enantioselectivity up to 20% 

ee was reached until this point it was the highest enantiomeric excess induced by monodentate 

ligands for this type of reaction. 51,53 

0.2 mol% [Rh(acac)(CO) 2] 

1 mol% (S)-66a 

O 

P Ph 

CO/H2 (50 bar) 

* 

benzene, 30 °C, 3 h 

(S)-66a 69 70 71 

+ 

iso-selectivity: 95% 

20% ee 

Scheme 21. Enantioselective hydroformylation in the presence of catalyst containing ligand 66a. 

Some years later the group of Stelzer reported the synthesis of secondary phosphine based on 

phosphepine scaffold 66 (R = H) in good yields. 54 The described achiral secondary phosphine 

was used as building block or precursor for various ligand systems. However, from practical 

point of view the approaches invented by Gladiali et al. and Stelzer et al. causes some 

difficulties with respect to up–scaling and industrial demands since expensive auxiliaries were 

used and a low overall yield of final ligand was achieved. 

Different attempts were reported on the synthesis of 2,2´–dimethylbinaphthyl 65 in an 

enantiomeric pure form. 55 On the one hand various chiral versions were described for C–C 

bond formation via Kumada coupling by exchange of triphenylphosphine by chiral ligands, 

but so far best enantioselectivity of 95% ee was reported by Ito et al. 56 Furthermore, few 

Suzuki coupling reactions were published with comparable low enantioselectivities (85% 

ee). 57 Although some excellent enantioselectivities were demonstrated by C–C coupling 

methods, the up–scaling of these methods is limited by the availability of applied ligands. On 

the other hand a more convenient two step pathway starting from enantiomeric pure 2,2´– 

binaphthol (98% ee) was lately established since nowadays the available of 2,2´–binaphthol is 

18 

O


feasible on large scale. 58,59 The updated synthesis of binaphthophosphepines starts with 

diesterification of enantiomerically pure 2,2´–binaphthol 72 with trifluoromethanesulfonic 

acid anhydride in the presence of pyridine (Scheme 22). 60 The corresponding diester was 

obtained in quantitative yield and subsequent nickel–catalyzed Kumada coupling with methyl 

magnesium bromide leads to 2,2´–dimethylbinaphthyl 65 in 95% yield. 61 Two different 

synthetic strategies were established to obtain 4,5–dihydro–3H–dinaphtho[2,1–c;1´,2´– 

e]phosphepine ligands 66. On the one hand, double metallation of 2,2´–dimethylbinaphthyl 65 

with n–butyl lithium in the presence of tmeda (N,N,N´,N´–tetramethylethylenediamine) 

followed by quenching with commercially available dichlorophosphines gives ligands such as 

66a (P–phenyl) and 66b (P–t–butyl) in 60–83% yield. 

1. n-BuLi / tmeda 

2. Cl 2PNEt 2 

69 

HCl 

P NEt 2 

65 

OH 

OH 

72 

(CF 3SO 2) 2O / Py 

NiCl 2(dppp) / MeMgBr 

CH 3 

CH 3 

P Cl 

1. n-BuLi / tmeda 

2. Cl 2PR 

RMgX or RLi 

Scheme 22. Synthetic approach to 4,5–dihydro–3H–dinaphtho[2,1–c;1´,2´–e]phosphepine developed 

by Beller et al. 

74 

P R 

66 

19


Both ligands have been synthesized on >10g–scale. In the second procedure the dilithiated 

2,2´–dimethylbinaphthyl 65 is quenched with diethylaminodichlorophosphine to produce the 

phosphepine 73 62 which, upon treatment with gaseous HCl is converted into 4–chloro–4,5– 

dihydro–3H–dinaphtho[2,1–c;1´,2´–e]phosphepine 74 in 80% yield. This enantiomerically 

pure chlorophosphine is easily coupled with various Grignard or lithium reagents to render a 

broad selection of ligand 66. The limited number of commercially available 

dichlorophosphines and the large diversity of Grignard compounds make the access through 

4–chloro–4,5–dihydro–3H–dinaphtho[2,1–c;1´,2´–e]phosphepine 74 the route of choice to a 

library of ligands 66 (Scheme 23). 59 

OCH 3 

CF 3 

OCH 3 

OCH 3 

OCH 3 

OCH 3 

F F 

P R 

F 

F 

F F 

66c 66d 66e 

66a 66f 

66g 66h 

N 

D 

D D 

D 

D 

t-Bu t-Bu 

H 3C 

CH 3 

CH 3 

F 

H 3C CH 3 

N N 

N 

CH 3 

66k 

66i 66j 

66m 

66n 

66p 66q 66s 

66t 

66r 

66v 66w 

66x 66y 

66z 

N 

CH 3 

F 

H 3C 

F 

CH 3 

CH 3 

20 

F 

N(CH 3) 2 

Schema 23. Ligand library based on 4,5–dihydro–3H–dinaphtho[2,1–c;1´,2´–e]phosphepine motif. 

Noteworthy, parallel to the work of Beller et al. the group of Zhang described a similar 

synthetic approach, but using monodentate system as intermediate since their research mainly 

66 

66b


focused on bidentate ligands and preliminary unpromising results with ligand 66b in 

asymmetric hydrogenations were obtained (Scheme 24). 63 Extraordinary enantioselectivity 

was obtained for bidentate ligands containing the phosphepine moiety (Scheme 24, 75–77). 64 

P 

P 

Binaphane (75) 

CH 3 

CH 3 

65 

NHAc 

1. n-BuLi 

2. PCl 3 

1. 50-60% 

2. 40% 

COOMe 

P Cl 

1 mol% [Rh(cod)]SbF 6 

2 mol% 66b 

H 2 (60 psi) 

MeOH, r.t., 24 h 

H 

P t Bu 

Bu P t H 

t-BuMgBr 

60% 

59 60 

Binapine (76) 

74 

NHAc 

* 

COOMe 

P 

6% ee 

Fe 

P 

P 

66b 

f-Binaphane (77) 

Scheme 24. Synthesis of 4,5–dihydro–3H–dinaphtho[2,1–c;1´,2´–e]phosphepine by a protocol 

established by Zhang et al. 

Nevertheless, the group of Beller applied tool box 66 in various catalytic reactions. First set of 

catalytic experiments with ligand library 66 were dedicated to the rhodium–catalyzed 

asymmetric hydrogenation of α–amino acid precursors. 59c Here, methyl (Z)–α– 

acetamidocinnamate 39 and methyl α–acetamidoacrylate 59 were chosen as model systems. 

Representative results are summarized in Table 1 and Table 2. Surprisingly, initial experiment 

with different solvents pointed out a benefit for toluene even if toluene is an unusual solvent 

for hydrogenation purpose, due to catalyst inhibition. 65 However, best enantioselectivities up 

to 95% ee were achieved in toluene with high catalyst activities (TOF 1000–6000 h -1 ). In 

some cases a slight improvement of enantioselectivity and reactivity was found when catalytic 

amount of tenside sodium dodecylsulfonate (SDS) were placed in the reaction (Table 1, 

entries 2 and 3). Analysis of presented results indicates a crucial influence of substitution 

pattern at the phosphorous atom. Best enantioselectivities were obtained with aryl systems, 

while alkyl derivatives lead to low enantiomeric excess (Table 1, entry 1). In the case of 

asymmetric hydrogenation of substrate 39 a detailed study of various ligands with 

21


substituted–aryl groups connected to the phosphorous demonstrated no significant change in 

enantioselectivity, when electron–donating or electron–withdrawing functionalities were sited 

in the para–position. Analogous substitution in ortho–position decreased the 

enantioselectivity (Table 1). For the reduction of 59 a converse behaviour was attained since 

substitution on the aromatic unit improved the enantioselectivity (Table 2). 

Table 1. Asymmetric hydrogenation of 39 in the presence of catalysts containing ligand class 66. 

P R 

66a: R = Ph 

66b: R = t-Bu 

66c: R = 4-CH 3O-C 6H 4 

66e: R = 3,4-(CH 3O) 2C 6H 3 

66i: R = 2-CH 3O-C 6H 4 

66n: R = 2-F-C 6H 4 

66q: R = 3,5-(t-Bu) 2C 6H 3 

66s: R = 2-Naphthyl 

Ph 

NHAc 

COOMe 

1 mol% [Rh(cod) 2]BF 4 

2 mol% 66 

H 2 (1 bar) 

25 °C 

Ph 

39 40 

Entry Ligand Solvent t/2 [min] Conversion [%] ee [%] (R) 

1 

66b Toluene 31 > 99 20 

2 66a Toluene 50 > 99 90 

3 [a] 

66a Toluene + SDS 33 > 99 95 

4 66c Ethyl acetate 4 > 99 88 

5 [a] 

66q Toluene + SDS 2 > 99 95 

6 66i Toluene 59 > 99 64 

7 [a] 

66n Toluene + SDS 53 > 99 91 

8 [a] 

66s Toluene + SDS 50 > 99 94 

9 66e Toluene - > 99 93 

[a] 

20 mol% SDS (sodium dodecylsulfonate). 

Table 2. Asymmetric hydrogenation of 59 in the presence of catalysts containing ligand class 66. 

P R 

66a: R = Ph 

66c: R = 4-CH 3O-C 6H 4 

66i: R = 3-CH 3O-C 6H 4 

66n: R = 2-F-C 6H 4 

66q: R = 3,5-(t-Bu) 2C 6H 3 

NHAc 

COOMe 


2 mol% 66 

H 2 (1 bar) 

22 

NHAc 

COOMe 

NHAc 

COOMe 

25 °C 

59 60 

Entry Ligand Solvent t/2 [min] Conversion [%] ee [%] (R) 

1 66a Toluene 18 > 99 67 

2 66c Ethyl acetate 2 > 99 51 

3 66q Toluene 1 > 99 94 

4 [a] 

66n Toluene + SDS 20 > 99 84 

5 [a] 

66i Toluene + SDS 17 > 99 86 

[a] 

20 mol% SDS (sodium dodecylsulfonate). 

Next the potential of ligand library 66 was tested in the asymmetric hydrogenation of 

dimethyl itaconate 56 (Table 3). Here, best reaction outcome was obtained in


dichloromethane as solvent, even if to some extend lower enantioselectivities up to 88% ee 

were observed. 

Table 3. Asymmetric hydrogenation of dimethyl itaconate 56. 

P R 

66a: R = Ph 

66c: R = 4-CH 3O-C 6H 4 

66i: R = 3-CH 3O-C 6H 4 

66n: R = 2-F-C 6H 4 

66q: R = 3,5-(t-Bu) 2C 6H 3 

66s: R = 2-Naphthyl 

COOMe 

COOMe 


2 mol% 67 

H 2 (1 bar) 

CH 2Cl 2, 25 °C 

56 57 

Entry Ligand Conversion [%] t/2 [min] ee [%] (S) 

1 66a > 99 56 86 

2 66c > 99 - 86 

3 66q > 99 16 83 

4 66n 86 16 77 

5 66s 29 34 70 

6 66i > 99 - 88 

COOMe 

23 

COOMe 

A more convincing approach to enantiopure itaconic acid was quite recently reported by 

Gladiali and co–workers (Scheme 25). 66 Excellent enantioselectivities up to 97% ee were 

attained when subjecting itaconic acid to a rhodium–catalyzed transfer hydrogenation under 

mild reaction conditions in the presence of well–defined cationic [Rh(nbd)(66a)2] + 

complexes. As suitable source of hydrogen formic acid was chosen since carbon dioxide 

arises as only side product. Notably, by utilizing the corresponding dimethyl ester or the two 

possible monomethyl esters under same conditions a decrease of enantioselectivity was 

noticed, accompanied by a switch of product configuration. Furthermore, a comparative study 

was carried out by testing several monodentate as well as bidentate ligands. The presented 

results pointed out the potential of this ligand since only a BINAP complex achieved similar 

enantioselectivity. 

P Ph 

66a 

COOR 1 

COOR 2 

Scheme 25. Transfer hydrogenation of itaconic acid derivatives. 

1.5 mol% [Rh(nbd)(66a) 2]BF 4 

HCOOH/NEt 3 (5:2) 

DMSO, 22 °C, 4 h 

53: R 1 = R 2 = H: 97% ee (S), conv. >99% 

56: R 1 = R 2 = Me: 13% ee (R), conv. 57% 

COOR2 COOR 

* 

1


The application of ligand class 66 was furthermore demonstrated in the hydrogenation of N– 

acyl enamide 78 by the group of Reetz (Scheme 26). 67 The obtained enantioselectivities are 

comparable low, but surprisingly the tert–butyl–substituted ligand 66b (conversion: 94%; 

enantiomeric excess: 24% (R)) showed better selectivity and conversion than the phenyl– 

substituted ligand 66a (conversion: 50%; enantiomeric excess: 14% (R)), while in other 

benchmark tests such as the asymmetric hydrogenation of α–amino acid precursors, dimethyl 

itaconate and β–ketoesters always the opposite behaviour was observed. However, in 

combination with BINOL–derived phosphites or phosphonites a significant enhancement of 

enantioselectivity up to 89% ee was found. This combinatorial approach displayed 

impressively one advantage of monodentate phosphorous ligands, as the reaction outcome can 

easily be tuned by different combination of ligands. 42m,68 

P R 1 

66a: R 1 = Ph 

66b: R 1 = t-Bu 

O 

P R 

O 

2 

48a: R2 = CH3 47a: R2 = OCH3 Scheme 26. Asymmetric hydrogenation of N–acyl enamides. 

NHAc 0.2 mol% [Rh(cod) 2]BF4 NHAc 

0.2 mol% L1 / 0.2 mol% L2 H2 (1.3 bar) 

CH2Cl2, 30 °C, 20 h 

78 78 

L 1 = L 2 = 66a: 14% ee (R), conv. 50% 

L 1 = L 2 = 66b: 24% ee (R), conv. >99% 

L 1 = L 2 = 47a: 76% ee (R), conv. >99% 

L 1 = L 2 = 48a: 76% ee (R), conv. >99% 

combinatorial approach 

L 1 = 66a, L 2 = 47a: 57% ee (R), conv. >99% 

L 1 = 66b, L 2 = 47a: 89%ee (R), conv. >99% 

L 1 = 66a, L 2 = 48a: 53% ee (R), conv. >99% 

L 1 = 66b, L 2 = 48a: 87% ee (R), conv. >99% 

Following the original work of Reetz et al. the group of Beller investigated the reaction in 

presence of chiral monodentate 4,5–dihydro–3H–dinaphtho[2,1–c;1´,2´–e]phosphepine 66 in 

more detail (Table 4). 59f After optimization of different reaction parameters 

enantioselectivities up to 93% ee were achieved with rhodium catalyst containing 2 equiv. of 

ligand 66a. As shown in Table 4 the enantioselectivity is largely dependent on the nature of 

the substituent at the phosphorous atom. Further improvement up to 95% ee, which is up to 

now the highest enantiomeric excess obtained with monodentate phosphine ligands for this 

purpose, was attained when the substrate structure was modified by introduction of electron– 

donating groups at the aromatic part of the substrate, while substrates containing electron– 

withdrawing groups were hydrogenated with somewhat lower enantioselectivities. 

24


Table 4. Extension of asymmetric hydrogenation of N–acyl enamides. 

P R 

66a: R = Ph 

66b: R = t-Bu 

66c: R = 4-CH 3O-C 6H 4 

66e: R = 3,4-(CH 3O) 2-C 6H 3 

66h: R = 4-F-C 6H 4 

66i: R = 2-CH 3O-C 6H 4 

66m: R = 3,5-(CH 3) 2-C 6H 3 

66p: R = 4-F 3C-C 6H 4 

NHAc 

Entry Ligand Conversion [%] 


2.1 mol% 66 

H 2 (2.5 bar) 

toluene, 30 °C, 6 h 

25 

NHAc 

* 

78 79 

ee [%] 

1 66a >99 93 (R) 

2 66p >99 72 (R) 

3 66h >99 88 (R) 

4 66m >99 87 (R) 

5 66c >99 93 (R) 

6 66i >99 63 (R) 

7 66e >99 90 (R) 

8 66b >99 16 (S) 

Apart from α–amino acids β–amino acids received significant attention since they are useful 

building blocks for pharmaceuticals. Hence the groups of Beller and Gladiali reported on the 

successful application of ligand class 66 in the rhodium–catalyzed asymmetric hydrogenation 

of β–dehydroamino acids derivatives to give optical active β–amino acids derivatives. 69 First 

experiments emphasized a necessity of different reaction conditions for the E– and Z–isomer 

(Table 5). Good enantioselectivity (79% ee (R)) for the E–isomer was obtained by using 2– 

propanol at 2.5 bar hydrogen pressure, while higher pressure (50 bar) in ethanol was 

worthwhile for the Z–isomer (92% ee (R)). Noteworthy, a switch of product configuration 

was observed depending on the nature of the double bond, which has been scarcely 

reported. 70 Furthermore, a higher reaction rate was monitored for the Z–isomer, while 

converse behaviour was demonstrated for most other catalysts. 71 After separate optimization 

of reaction parameters for both isomers the ligand library 66 was subjected to catalytic 

reaction. Surprisingly, in the case of hydrogenation of E–61a good enantioselectivity was 

achieved with alkyl ligand 66b, while for other catalytic reactions (vide supra) poor to 

moderate enantioselectivities were reported (Table 5, entry 6). However, in the hydrogenation 

of the corresponding Z–isomer the catalyst containing ligand 66b was completely inactive. 

Here best enantiomeric excess was reached by ligand 66a (Table 5, entry 1). The usefulness 

of this concept was confirmed on the hydrogenation of several β–dehydroamino acids 

derivatives. An improved enantioselectivity of 94% ee was attained by replacement of methyl 

ester by ethyl ester. Some mechanistical attempts showed the necessity of 2 equiv. ligands per


metal, which is in agreement with previous findings by Knowles et al. This circumstance 

offers the possibility for a combinatorial ligand approach. Beller and Gladiali et al. adopted 

this concept and combined ligand 66a with achiral phosphorous ligands. Unfortunately, no 

significant positive effect was attained. 

Table 5. Hydrogenation of E–61a and Z–61a with different 4,5–dihydro–3H–dinaphtho[2,1–c;1´,2´– 

e]phosphepines 66. 

P R 

66a: R = Ph 

66b: R = t-Bu 

66c: R = 4-CH 3O-C 6H 4 

66d: R = 3-CH 3O-C 6H 4 

66e: R = 3,4-(CH 3O) 2-C 6H 3 

66m: R = 3,5-(CH 3) 2-C 6H 3 

Entry Ligand Isomer [a] 

O O 

NH O 

[Rh(cod) 2]BF4 + 2.1 (66) 

NH 

OMe 

Z-61a 

H 2 (50 bar), EtOH, 10 °C, 24 h 

O O 

NH 

[Rh(cod) 2]BF4 + 2.1 (66) 

NH 

MeO O 

E-61a 

Conv. [%] 

H 2 (2.5 bar), 2-PrOH, 10 °C, 24 h 

ee [%] 

Isomer [b] 

Conv. [%] 

O 

(S)-62a 

O 

(R)-62a 

ee [%] 

1 66a E–61a >99 79 (R) Z–61a >99 92 (S) 

2 66m E–61a 80 69 (R) Z–61a >99 80 (S) 

3 66c E–61a >99 88 (R) Z–61a >99 86 (S) 

4 66d E–61a 91 81 (R) Z–61a 90 40 (S) 

5 66e E–61a >99 90 (R) Z–61a >99 89 (S) 

6 66b E–61a >99 87 (R) Z–61a 3 60 (S) 

In addition, the group of Beller carried out an enantioselective reduction of enol carbamates, 

which allows an alternative approach to chiral alcohols. 72 Pioneering work in the field of 

asymmetric hydrogenation of enol carbamates has been reported by Feringa, de Vries, 

Minnaard and co–workers who have scored enantioselectivities up to 98% ee with rhodium- 

catalysts containing monodentate phosphoramidites (MonoPhos–family). 41l,73 Utilizing 

compound 80 as model substrate various reaction parameters were investigated in detail and 

enantioselectivities up to 96% ee were achieved with an in situ catalyst composed of 

[Rh(cod)2]BF4 and ligand 66a. Noteworthy, high thermal stability of the catalyst in the range 

of 10–90 °C was noticed with respect to enantioselectivity (94–96% ee). With these suitable 

conditions ligand library 66 was subjected to a series of enol carbamates. Despite all attempts 

only 66a displayed extraordinary selectivity. 

OMe 

26 

OMe


Table 6. Hydrogenation of compound 80 with different 4,5–dihydro–3H–dinaphtho[2,1–c;1´,2´– 

e]phosphepines 66. 

P R 

66a: R = Ph 

66b: R = t-Bu 

66c: R = 4-CH 3O-C 6H 4 

66k: R = i-Pr 

66i: R = 2-CH 3O-C 6H 4 

66m: R = 3,5-(CH 3) 2-C 6H 3 

66p: R = 4-F 3C-C 6H 4 

O 

N 

O 

80 

[Rh(cod) 2]BF 4 + 2.1 (66) 

H 2 (25 bar) 

MeOH, 25 °C, 6 h 

Entry Ligand Conv. [%] Yield [%] ee [%] 

1 66a >99 >99 96 (S) 

2 66p 40 40 28 (S) 

3 66m >99 >99 66 (S) 

4 66c >99 >99 72 (S) 

5 66i >99 >99 51 (S) 

6 66k 40 40 12 (S) 

7 66c 41 41 50 (R) 

N 

O O 

* 

While the group of Beller mainly focused on the variation of substituent at the phosphorous in 

4,5–dihydro–3H–dinaphtho[2,1–c;1´,2´–e]phosphepines Widhalm et al. reported efforts on 

the α–substitution adjacent to the phosphorous atom (Scheme 27). 74 Due to the rise of new 

stereocenters which are closer to the metal a better transfer of chiral information was 

assumed. Starting from 66a, which was synthesized according to literature procedures, the 

corresponding sulfide 82 was prepared. In addition, a deprotonation protocol was established 

which offers a huge variety of mono– as well as disubstituted ligands after reduction since 

simple quenching with electrophils are displayed. The substitution was highly stereoselective, 

because only single diastereomers were obtained. With these ligands in hand a comparative 

study was carried out to explore the influence of α– and α,α´–substitution. In the rhodium– 

catalyzed hydrogenation of 14a and 39 only with the α,α´–dimethyl ligand 86b comparable 

enantioselectivities to unsubstituted system were reported, while monosubstituted and other 

disubstituted representatives lead to moderate selectivity. Interestingly, similar 

enantioselectivity and activity was attained by utilization of only 1 equiv. of ligand with 

respect to rhodium. Noteworthy, substitution gained a switch of product configuration. 

27 

81

86a: R 1 = R 2 = TMS 

86b: R 1 = R 2 = Me 

86c: R 1 = R 2 = Et 

86d: R 1 = R 2 = Bn 

86e: R 1 = R 2 = i-Pr 

Ph 

NHAc 

COOR 3 


R 1 

P Ph 

84a: R 1 = TMS 

84b: R 1 = Me 

84c: R 1 = Et 

84d: R 1 = Bn 

84e: R 1 = i-Pr 

1 mol% [Rh] 

2 mol% 66a or 86b 

H 2 (3 bar) 

r.t. 

Raney-Ni 

R 1 

CH3 CH3 P Ph 

R 2 

86 

Ph 

65 

1) n-BuLi 

2) Cl 2PPh 

3) S 8 

Raney-Ni 

* NHAc 

COOR 3 

R 

S 

P 

Ph 

1 

Scheme 27. Synthesis of α–substituted and α,α´–substituted phosphepine ligands. 

S 

P 

Ph 

82 

1) t-BuLi 

2) (R 1)X 

1) t-BuLi 

2) R 2 X 

R 

S 

P 

Ph 

1 

R 2 

S 

P 

Ph 

R 1 

83a 83b 

85 

15a: R 3 = H 

[Rh(cod)Cl] 2/NaOCl 4 , MeOH/CH 2Cl 2 

ligand 66a: 91% ee (R), conv. 99% 

ligand 86b: 91% ee (S), conv. 99% 

40: R 3 = Me 

[Rh(cod) 2]BF 4 , 2 mol% ligand, toluene 

ligand 66a: 85% ee (R), conv. 99% 

ligand 86b: 55% ee (S), conv. 98% 

28


2.2.1. Monodentate ligands based on 4,5–dihydro–3H–dinaphtho[2,1–c;1´,2´– 

e]phosphepine scaffold in asymmetric synthesis 

Apart from numerous attempts on asymmetric hydrogenation of C–C double bonds further 

asymmetric catalytic applications have been demonstrated the usefulness of monodentate 

phosphines based on 4,5–dihydro–3H–dinaphtho[2,1–c;1´,2´–e]phosphepine motif e.g. the 

ruthenium-catalyzed asymmetric hydrogenation of β–ketoesters, 75 asymmetric borylation, 

asymmetric Suzuki coupling reactions catalyzed by palladium complexes, the Pd–catalyzed 

umpoled–allylation of aldehydes 76 and the Pt–catalyzed alkoxycyclization of 1,5–enynes. 77 

The ligand itself without any metal has been proven as efficient organocatalyst for the 

enantioselective acylation of diols, [3+2] cycloadditions and [4+2] annulations (Scheme 

27). 78 

CHO 

NHAc 

OH 

R 

COOMe 

R1 COOR 

48% ee 95% ee 95% ee 

Hydroformylation 

Gladiali et al. 

Beller et al. 

Hydrogenation 

Beller et al. 

Transfer Hydrogenation 


Hydrogenation 

Beller et al. 

ROOC 

Ph 

ROOC 

H 

HO 

85% ee 

Alkoxycyclization 

Michelet, Gladiali, Genet et al. 

Ph 

Ph 

OH 

Ts 

N 

Ph 

Allylation 

Zanoni et al. 

COOEt 

COOEt 

99% ee 

[4+2] Annulation 

of Imines with Allenes 

Fu et al. 

CO2Et O 

R 

R 1 

70% ee 

95% ee 

[3+2] Cycloaddition 

of Allenes with Enones 

Fu et al. 

Ph OH 

P R 

Ph OAc 

22% ee 

Acylation 

Vedejs et al. 

Scheme 27. Applications of ligand class 66 in asymmetric synthesis. 

66 

COOR 

COOR 1 

97% ee 

Hydrogenation 

Beller et al. 

Transfer Hydrogenation 


NHAc 

95% ee 

Hydrogenation 

Beller et al. 

R 1 

NHAc 

COOR 

94% ee 

Hydrogenation 

Beller et al. 

O 

O 

96% ee 

Hydrogenation 

Beller et al. 

NR 1R 2 

29


2.3. Concluding remarks 

The rediscovery of monodentate phosphorous ligands displayed a milestone in asymmetric 

hydrogenation since high activities, enantioselectivities and ligand combinations for tuning 

the outcome of the reaction are feasible. In the case of chiral monodentate phosphines until 

now only a few number of ligands have been proven to entrance enantioselectivities above 

90% ee. Here ligands with 4,5–dihydro–3H–dinaphtho[2,1–c;1´,2´–e]phosphepine structure 

motif demonstrated excellent enantioselectivities up to 96% ee in several catalytic 

applications. However, the discovery of new effective phosphines will be an important 

challenge for future research due to there superior stability in comparison to monodentate 

phosphoramidites, phosphites and phosphonites. 

30


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32


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33


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38

3. Reduction of unsaturated compounds with homogeneous iron catalysts 39 

3. Reduction of unsaturated compounds with homogeneous iron 

catalysts 

Stephan Enthaler, Kathrin Junge, and Matthias Beller*, in B. Plietker (Ed.) “Iron catalysis in 

organic chemistry“ Wiley VCH, Weinheim, 2008. 

Contributions 

The subchapter “Hydrosilylation” was written by Dr. K. Junge.

3. Reduction of unsaturated compounds with homogeneous iron catalysts 


Stephan Enthaler, Kathrin Junge, and Matthias Beller 

Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Str. 29a, 

18059 Rostock, Germany. Fax: 49-381-1281-5000; Tel: 49-381-1281-113; E-mail: 

matthias.beller@catalysis.de 

3.1. Introduction 

Within the different molecular transformations reduction processes plays one of the major 

roles in organic chemistry. Apart from stoichiometric reactions, transition metal catalyzed 

reactions offer an efficient and versatile strategy and present a key technology for the 

advancement of “green chemistry”, specifically for waste prevention, reducing energy 

consumption, achieving high atom efficiency and creating advantageous economics. 1 Among 

the most popular and extensive studied catalytic reactions with respect to industrial 

applications is the hydrogenation of unsaturated compounds containing C=C, C=O and C=N 

bonds since addition of molecular hydrogen provides high atom efficiency. 2 In this regard, for 

activation of the molecular hydrogen or hydrogen donors, transition metal catalysts are 

essential. Commonly expensive and rare late transition metals (Ir, Rh or Ru) are applied as 

catalyst core. Therefore, substitution by ubiquitous available, inexpensive and less toxic 

metals is one of the major challenges for future research. Consequently, the use of iron 

catalysts is especially desirable. 3 This chapter will summarize the impact of iron catalysts on 

hydrogenation and hydrosilylation chemistry and mainly directed to the reduction of C=C, 

C=O and C=N bonds. Further catalytic applications were summarized elsewhere e.g. 

reduction of nitro compounds or dehalogenations. 4 

3.2. Hydrogenation of carbonyl compounds 

The relevance of carbonyl hydrogenation processes is impressively emphasized by the broad 

scope of applications for example as building blocks and synthons for pharmaceuticals, 

agrochemicals, polymers, synthesis of natural compounds, auxiliaries, ligands and key 

intermediates in organic syntheses (Scheme 1). 5 

40


O 

N 

Orphenadrin (1) 

anticholinergic drug 

HO 

OH 

HCl 

H 

N OMe 

OMe 

(R)-Denopamine-Hydrochloride (2) 

β 1-receptor antagonist 

Scheme 1. Selected pharmaceuticals based on chiral alcohols. 6 

F 

OH 

N 

BMS 181100 (3) 

antipsychotica 

N 

N N 

In the past this field has been dominated by ruthenium, rhodium and iridium catalysts with 

extraordinary activities and furthermore superior enantioselectivities, however some 

investigations were carried out with iron catalysts. Early efforts were reported on the 

successful use of hydridocarbonyliron complexes (HFem(CO)n - ) as reducing reagent for α,β- 

unsaturated carbonyl compounds, dienes and C=N double bonds, albeit complexes were used 

in stoichiometric amounts. 7 The first catalytic approach was presented by Markó and coworkers 

on the reduction of acetone in the presence of Fe3(CO)12 or Fe(CO)5. 8 In this reaction 

the hydrogen is delivered by water under more drastic reaction conditions (100 bar, 100 °C). 

Addition of NEt3 as co-catalyst was necessary to obtain reasonable yields. The authors 

assumed a reaction of Fe(CO)5 with hydroxide ions to yield HFe(CO)4 - under liberation of 

carbon dioxide since basic conditions are present, and excluded formation of molecular 

hydrogen via water gas shift reaction. HFe(CO)4 - is believed to be the active catalyst, which 

transferred the hydride to the acceptor. The presented catalyst displayed activity in the 

reduction of several ketones and aldehydes (Scheme 2). 9 

R 1 

O 

R 2 

10 mol% Fe(CO) 5 

NEt 3 

R 1 

OH 

100 bar (H2:CO 98.5:1.5) 

4 150 °C, 3 h 

5 

R 2 

5a: R 1 = CH 3; R 2 = CH 3: conv.: >99% 

5b: R 1 = C 6H 5; R 2 = CH 3: conv.: 62% 

5c: R 1 = i-Bu; R 2 = CH 3: conv.: 30% 

5d: R 1 = C 6H 5; R 2 = H: conv.: 95% 

5e: R 1 = n-Pr; R 2 = H: conv.: 98% 

6: cyclohexanone: conv.: >99% 

Scheme 2. Reduction of ketones and aldehydes by using the Fe(CO)5/NEt3 system according 

to Markó et al. 

Later on, the group of Vancheesan referred on transfer hydrogenation of ketones utilizing 2propanol 

or 1-phenylethanol as hydrogen source (Scheme 3). 10 A phase transfer catalyst was 

essential to support the hydrogenation catalyst Fe3(CO)12 or Fe(CO)5 since a liquid-liquid 

biphasic system was used as solvent. Under mild reaction conditions several ketones were 

hydrogenated to the corresponding alcohols with turnover frequencies up to 13 h -1 . 

Mechanistic investigations indicated a similar process as reported by Markó et al. 8 

41 

F


R 1 

O 

R 2 

4 mol% Fe 3(CO) 12 

PTC: BzEt 3NCl or Aliquat 336 

NaOH 

R 1 

OH 

4 

water/2-PrOH 

or water/1-phenylethanol 

28 °C, 2.5-3 h 

5 

R 2 

5b: R 1 = C 6H 5; R 2 = CH 3: yield: 36% 

5f: R 1 = 4-Cl-C 6H 4; R 2 = CH 3: yield: 42% 

5g: R 1 = 4-Me-C 6H 4; R 2 = CH 3: yield: 28% 

5h: R 1 = Et; R 2 = CH 3: yield: 20% 

6: cyclohexanone: yield: 78% 

Schema 3. Phase transfer catalyzed transfer hydrogenation of ketones by Vancheesan et al. 

More recently, Gao et al. reported in a special chinese journal an asymmetric transfer 

hydrogenation (Scheme 4) based on [Et3NH][HFe3(CO)11] and chelating chiral ligands. 11 In 

the presence of enantiopure diaminodiphosphine iron catalysts they claim good conversion 

and enantioselectivity up to 98% ee (substrate 5j). 

NH HN 

PPh 2 Ph 2P 

(S,S)-6 

(R,R)-6 

R 1 

O 

R 2 

1 mol% [Et 3NH][HFe 3(CO) 11] 

ligand 6 

6 mol% KOH 

R 1 

2-PrOH 

4 45-82 °C, 3-21 h 

5 

OH 

* 

R 2 

ligand: (S,S)-6 

5b: R 1 = C 6H 5; R 2 = CH 3: 56% ee (R), yield: 92% (82 °C, 7 h) 

5i: R 1 = C 6H 5; R 2 =C(CH 3) 3: 93% ee (S), yield: 19% (82 °C, 7 h) 

5j: R 1 = CH(C 6H 5) 2; R 2 =CH 3: 98% ee (S), yield: 18% (65 °C, 21 h) 

5k: R 1 = C 6H 5; R 2 =Cy: 78% ee (S), yield: 73% (82 °C, 17 h) 

ligand: (R,R)-6 

5m: R 1 = C 6H 5; R 2 = C 2H 5: 72% ee (S), yield: 87% (45 °C, 4.5 h) 

5n: R 1 = C 6H 5; R 2 = CH(CH 3) 2: 78% ee (S), yield: 98% (45 °C, 3 h) 

Schema 4. Enantioselective transfer hydrogenation catalyzed by iron complexes by Gao et al. 

In 2006 we reported the application of an easy to adopt in situ concept composed of an iron 

source e.g. FeCl2 or Fe3(CO)12, monodentate phosphines and tridentate nitrogen ligands in the 

transfer hydrogenation of aliphatic and aromatic ketones using 2-propanol as hydrogen source 

(Scheme 5). 12 The influence of different reaction parameters on the reduction of model 

substrate acetophenone 5b were studied in detail. A crucial influence of base and base 

concentration was displayed since only sodium isopropoxide gave reasonable amount of 

product. In comparison to ruthenium-based transfer hydrogenations a higher temperature is 

necessary. Notably, the advantage of this in situ concept is underlined by easy tuneability of 

the iron catalyst, due to the broad availability of simple phosphines and amines. Plenty of 

phosphorous and amine ligands were subjected to the model reaction. However, best results 

were found with a catalyst composed of Fe3(CO)12, triphenylphosphine and 2,2´:6´,2´´terpyridine 

or, surprisingly, 3 equiv. of pyridine with respect to iron. The later one resembles 

42


a straightforward catalyst regarding to industrial applications. After several optimization steps 

an active catalyst was developed which exhibit comparable activity to Ru3(CO)12 based 

catalysts and was successfull for the reduction of several ketones with good to excellent 

conversions. 13 

R 1 

O 

4 

R 2 

0.5 mol% FeCl 2 

0.5 mol% PPh 3/0.5 mol% TerPy 

25 mol% NaO-i-Pr 

2-PrOH, 100 °C, 7 h 

R 1 

OH 

5 

R 2 

5b: R 1 = C 6H 5; R 2 = CH 3: yield: 95% 



5m: R 1 = C 6H 5; R 2 = C 2H 5: yield: 92% 

5o: R 1 = 4-MeO-C 6H 4; R 2 = CH 3: yield: 75% 

5p: R 1 = 2-MeO-C 6H 4; R 2 = CH 3: yield: >99% 

5q: R 1 = C 6H 5; R 2 = CH 2Cl: yield: 8% 

5r: R 1 = Cy; R 2 = CH 3: yield: 93% 

5s: R 1 = t-Bu; R 2 = CH 3: yield: >99% 

Scheme 5. In situ catalyst based on FeCl2/terpy/PPh3 in the transfer hydrogenation of ketones. 

Very recently the effectiveness of FeCl2/terpy/PAr3 catalysts is proven in the hydrogenation 

of α-substituted ketones, which are interesting 1,2-diol precursors (Scheme 6). 14 Excellent 

yields, chemoselectivities and activities (TOF: up to 2000 h -1 ) were achieved under optimized 

conditions. 

R 1 

O 

1 mol% FeCl2 1 mol% P(4-F-C6H4) 3/1 mol% TerPy 

OR 

50 mol% NaOH 

2 

R 

2-PrOH, 100 °C, 1 h 

1 

OH 

7 8 

OR 2 

43 

8a: R 1 = C 6H 5; R 2 = CH 3: yield: 92% 

8b: R 1 = C 6H 5; R 2 = C 6H 5: yield: 94% 

8c: R 1 = C 6H 5; R 2 = 4-Cl-C 6H 4: yield: >99% 

8d: R 1 = C 6H 5; R 2 = 2,6-(i-Pr) 2C 6H 4: yield: 45% 

8e: R 1 = 4-Me-C 6H 5; R 2 = C 6H 5: yield: 99% 

8f: R 1 = 4-MeO-C 6H 5; R 2 = C 6H 5: yield: 85% 

8g: R 1 = t-Bu; R 2 = C 6H 5: yield: 22% 

Scheme 6. Reduction of α-substituted ketones in the presence of iron catalyst. 

Apart from synthetic aspects we attained some useful informations concerning the 

mechanism, even if the “real” catalyst structure is so far unclear. Various experiments proved 

the presence of a homogeneous catalyst. Following the original works on Ru-, Rh- or Ircatalyst, 

deuterated hydrogen donors were applied since for transfer hydrogenation two 

common mechanisms are established, nominated as direct hydrogen transfer via formation of 

a six-membered cyclic transition state constituted of metal, hydrogen-donor and -acceptor, 

and secondly the hydridic route, which is subdivided into two pathways, the monohydride and 

dihydride mechanism (Scheme 7). More specifically, the formation of monohydride-metalcomplexes 

promote an exclusive hydride transfer from carbon (donor) to carbonyl carbon 

(acceptor), whereas a hydride transfer via dihydride-metal-complexes leads to no accurate


prediction of hydride resting state, for the reason that the former hydride was transferred to 

carbonyl carbon (acceptor) as well as to the carbonyl oxygen (acceptor). 15 

O 

[M-H*] 

H 

O 

*H 

monohydride mechanism dihydride mechanism 

-acetone 

OH 

H* 

O 

[H-M-H*] 

H 

O 

*H 

-acetone 

OH 

H* 

44 

OH* 

H 

50% 50% 

Scheme 7. Hydridic route established for transfer hydrogenation with Rh-, Ru- and Ircatalysts. 

To specify the position and the nature of the transferred hydride, the reaction was performed 

with 2-propanol-d1 as solvent/donor, sodium 2-propylate as base and Fe3(CO)12/PPh3/TerPy 

as catalyst under optimized conditions. In the transfer hydrogenation of acetophenone a 

mixture of two deuterated 1-phenylethanols was obtained (Scheme 8, 9a and 9b). The ratio 

between 9a and 9b (85:15) indicated a specific migration of the hydride, albeit some 

scrambling was detected. However, the incorporation is in agreement with the monohydride 

mechanism, implying a formation of metal monohydride species in the catalytic cycle. 

O 

5b 

[Fe]/NaO-i-Pr 

2-PrOD, 100 °C 

O 

H 

D 

+ 

O 

D 

H 

9a: 85% 9b:15% 

Scheme 8. Deuterium incorporation catalyzed by Fe3(CO)12/terpy/PPh3 system under transfer 

hydrogenation conditions. 

Parallel to the work on in situ three component catalysts we developed a nature inspired in 

situ catalyst based on iron porphyrin complexes since a high stability of the complexes are 

known and inertness against oxygen and moisture is feasible. 16 The porphyrin catalysts 

achieved even higher activities than three component system in the transfer hydrogenation of 

ketones (Scheme 9). After optimization of reaction parameters turnover frequencies up to 642 

h -1 at low catalyst loadings (0.01 mol%) were attained. A ligand screening emphasized 

porphyrin 10 as module of a highly active catalyst and makes it suitable for further 

investigations on substrate variation. Various ketones were reduced in good to excellent 

yields. Notably, also naturally occurring hemin has been used in this study. Even if lower


activity was gained it is a worthwhile system, due to the abundance and easy handling. 

Advantageously, no pre-catalyst formation is necessary. 

N 

N 

N 

NH N 

N 

HN 

10 

N 

R 1 

O 

R 2 

0.17 mol% Fe 3(CO) 12 

0.5 mol% 10 

8.5 mol% NaO-i-Pr 

2-PrOH 

100 °C, 7 h 

R 1 

OH 


5b: R 1 = C 6H 5; R 2 = CH 3: yield: 94% 


5o: R 1 = 4-MeO-C 6H 4; R 2 = CH 3: yield: 72% 

5p: R 1 = 2-MeO-C 6H 4; R 2 = CH 3: yield: >99% 

5m: R 1 = C 6H 5; R 2 = C 2H 5: yield: 87% 

5r: R 1 = Cy; R 2 = CH 3: yield: 89% 

5s: R 1 = t-Bu; R 2 = CH 3: yield: 90% 

Scheme 9. Biomimetic transfer hydrogenation of ketones with iron porphyrin catalysts. 

Applying Fe porphyrin catalysts and 2-propanol as hydrogen donor various α-hydroxyl- 

protected ketones are reduced to the corresponding mono protected 1,2-diols in good to 

excellent yield after optimization (Scheme 10). 17 Remarkable, addition of small amounts of 

water (5–10 mol%) boosted the catalysts activity up to 2500 h -1 at low catalyst loadings (0.01 

mol%). 

Cl 

N 

Cl 

NH N 

Cl 

HN 

11 

Cl 

R 1 

O 

1 mol% FeCl 2 

1 mol% 11 

50 mol% NaOH 

2-PrOH, 100 °C, 2 h 

8a: R 1 = C 6H 5; R 2 = CH 3: yield: >99% 

8b: R 1 = C 6H 5; R 2 = C 6H 5: yield: 92% 

8c: R 1 = C 6H 5; R 2 = 4-Cl-C 6H 4: yield: >99% 

8d: R 1 = C 6H 5; R 2 = 2,6-(i-Pr) 2C 6H 4: yield: 74% 

8e: R 1 = 4-Me-C 6H 5; R 2 = C 6H 5: yield: >99% 

8f: R 1 = 4-MeO-C 6H 5; R 2 = C 6H 5: yield: 83% 

8g: R 1 = t-Bu; R 2 = C 6H 5: yield: 48% 

Scheme 10. Reduction of α-substituted ketones in the presence of iron porphyrin catalysts. 

OR 2 

3.3. Hydrogenation of Carbon-Carbon Double Bounds 

Since the 60 th of the last century tremendous efforts were undertaken in the field of 

homogeneous hydrogenation of C-C double bonds emphasized by innumerable reports and 

later on rewarded by integrations in several industrial processes (Scheme 11). However, an 

R 1 

OH 

R 2 

45 

OR 2


even broader use in industry is expected by the availability of similar active and selective 

hydrogenation catalysts containing inexpensive metals (e.g. Fe and Cu). 

HO 

OH 

O 

NH 2 

OH 

L-DOPA (12) 

anti Parkinson´s disease 

O 

SH 

N 

H COOH 

N-Acetylcystein (13) 

mucolytic therapy 

H 2N 

COOH 

H 

N COOMe 

O 

Aspartam (14) 

artificial sweetener 

O N 

O 

O 

Cl 

F 

46 

Flamprop-isopropyl (15) 

herbizide 

Scheme 11. Selected pharmaceuticals, which are accessible by asymmetric C-C double bond 

hydrogenation. 5,18 

Indeed iron catalysts are known to transfer hydrogen to C-C double bonds. Early examples 

were carried out with metal salts activated by aluminium compounds in the hydrogenation of 

non-funtionalized olefins at comparable mild reaction conditions (0–35 °C and low hydrogen 

pressure). 19 Some research groups focused on the application of iron carbonyls due to the 

easier removal of the carbonyl ligands, for generating an active site, compared to halogens 

and avoidance of activating reagents. 20 Unsaturated carboxylic acid derivatives, for instance 

methyl linoleate and methyl linolenate, which contain two or three non-conjugated double 

bonds, respectively, were described in the mid of the 1960s (Scheme 12). 21,22 As catalyst 

precursor Fe(CO)5 was utilized at high temperature. The authors proposed as first step an 

isomerization of the double bonds catalyzed by Fe(CO)5 to obtain various dienes or trienes. 

Hydrogenation process was observed in case of conjugated dienes to yield monoenes via an 

iron-carbonyl-diene complex 18, while dienes were formed for the hydrogenation of methyl 

linolenate 16. The activity of the system was improved, when the iron-carbonyl-dienecomplex 

18 is used as precursor instead of Fe(CO)5. Analysis of the reaction mixture 

displayed mononenes as major products with unselective double bond distribution 

accompanied by small amounts of fully saturated compounds. Later on, Cais and co-worker 

studied the reaction of methyl hexa-2,4-dienoate as a model for fatty acids in more detail and 

reported several mechanistic considerations. 23


(CH 2) 4CH 3 (CH 2) 7COOMe 

H 3C(H 2C) x 

16 

Fe(CO) 5 

(CH 2) yCOOMe 


cyclohexane, H 2 (28 bar), 180 °C, 7 h 

Fe(CO) 5 

H 3C(H 2C) 4 

H3C(H2C) x Fe 

(CH2) yCOOMe 

OC CO 

CO 18 

Scheme 12. Fe-catalyzed hydrogenation of methyl linoleate. 

17 

H 3C(H 2C) v 

47 

(CH 2) 7COOMe 

(CH 2) wCOOMe 

Tajima and Kunioka described the hydrogenation of conjugated diolefins, in particular 1,3butadiene 

in the presence of activated [CpFe(CO)2Cl]. 24 AlEt3 and PhMgBr were tested as 

activation reagents, thereby the AlEt3-activated complex showed the best performance. The 

authors proposed the formation of iron-alkyl species which undergoes hydrogenolysis to 

create an active metal-hydride. The composition of the final mixture is dominated by cis-but- 

2-ene and trans-but-2-ene (ratio ~1:1). Furthermore traces of 1-butene were observed, 

whereas the catalyst was completely inactive for the hydrogenation of the mono-olefin to 

yield n-butane. 

19 

2.5 mol% CpFe(CO) 2Cl 

6 mol% AlEt 3 or 8.8 mol% PhMgBr 

benzene, H 2, 40-45 °C, 6 h 

20a 

+ + 

20b 

AlEt 3 conversion: 99% 

20a: 2%; 20b: 46%;20c: 52% 

PhMgBr conversion: 85% 

20a: 1%; 20b: 38%; 20c: 37% 

Scheme 13. Hydrogenation of butadiene with CpFe(CO)2Cl (Cp = cyclopentadienyl). 

Nishiguchi and Fukuzumi reported on the transfer hydrogenation of 1,5-cyclooctadiene (cod) 

in the presence of catalytic amounts of FeCl2(PPh3)2 (10 mol%) at high temperature (up to 

240 °C). 25 As hydrogen source polyhydroxybenzenes, for instance pyrogallol, pyrocatechol or 

hydrochinone, have been proven to be superior for this reaction, while primary and secondary 

alcohols led to lower conversion. The hydrogenation of 1,5-cyclooctadiene led to cyclooctane 

20c


as main-product, but the unsaturated cyclooctene and isomerization products were also 

observed. 

Later on Wrighton and co-workers recognized a reactivity increase with respect to 

hydrogenation rate when Fe(CO)5 was treated with light. 26,27 The authors assumed an 

expulsion of one carbonyl ligand to form an unsaturated species induced by near-ultraviolet 

irradiation. After complexation of the olefin again activation by light removed another 

carbonyl ligand to allow hydrogen coordination/activation. A number of unsubstituted olefins 

(e.g. ethylene, propylene, cis-3-hexene, cyclopentene, cyclooctene), were hydrogenated to 

give alkanes in moderate yield (up to 50%), while the catalyst is inactive for sterical 

demanding olefins (e.g. 1,2-dimethylcyclohexene) or aldehydes and nitriles. Furthermore, 

acetylenes were subjected to this photo-catalyzed reduction. However, only low yield (


At the beginning of the 90 th of the last century a switch to iron catalysts stabilized by either 

phosphines or nitrogen ligands took place. Here, Bianchini and co-workers carried out a 

detailed comparative study on the transfer hydrogenation of α,β-unsaturated ketones by 

nonclassical trihydride iron, ruthenium and osmium complexes containing tetradentate 

phosphines (Scheme 15). 30,31 In the presence of cyclopentanol as hydrogen donor several α,β- 

unsaturated ketones were hydrogenated to the corresponding saturated ketones with good to 

excellent selectivity under mild reaction conditions (Scheme 15). In some cases, e.g. 

benzylideneacetone or 2,3-cyclohexenone, the unsaturated or saturated alcohols were formed 

by the catalyst 26, thereby also good selectivity was noticed. Noteworthy, no co-catalyst, e.g. 

base, was necessary to activate the catalyst or the hydrogen donor, which is needed for other 

catalyst systems. However, for carbonyl hydrogenation, e.g. acetophenone and 

cyclohexanone, the iron catalyst displayed only low activity. No activity was found for 

aldehydes and C=C systems without additional carbonyl functionality. 

P 

P1 P1 Fe 

P1 P 1 = PPh 2 

R R1 dioxane, 

R1 H 

H 

H 

26 

O 

1 mol% 26 

cyclopentanol 

80 °C, 1-7 h 

O 

OH 

OH 

R 

+ 

R R1 + 

R R1 A B C 

27a: R = C 6H 5; R 1 = CH 3: conv.: 95%, B: 95% 

27b: R = C 6H 5; R 1 = C 6H 5: conv.: 30%, A: 30% 

27c: R = CH 3; R 1 = C 6H 5: conv.: 7%, A: 7% 

27d: R = CH 3; R 1 = C 2H 5: conv.: 19%, A: 19% 

27e: R = CH 3; R 1 = CH 3: conv.: 100%, A: 100% 

28: 2-cyclohexene: conv.: 72%, B: 44%, C: 28% 

29: 2-cyclopentene: conv.: 100%, A: 84%, B: 16% 

Scheme 15. Application of nonclassical iron trihydride complex in transfer hydrogenation 

according to Bianchini and co-workers. 

Reduction of styrene was reported by Kano et al. using NaBH4 as hydrogen source in the 

presence of iron porphyrin complex 30 (Scheme 16). 32 Good turnover frequencies up to 81 h -1 

and good chemoselectvities are obtained in protic solvents with catalyst loading of 1 mol% at 

room temperature. The reaction has been proven to be a radical process since to some extent 

2,3-diphenylbutane was detected. A similar approach was carried out by Sakaki and co- 

workers on the hydrogenation of α,β-unsaturated esters, who reported improvement of the 

catalyst activity (turnover frequency, tof = 4580 h -1 ). 33 A detailed study of the reaction 

mechanism displayed a crucial influence of the protic solvent because the hydride is assigned 

by NaBH4 and the proton by methanol. 

49


N N 

Fe 

N N 

+ 

Cl - 

30 

O 

OEt 

0.02 mol% 30 

200 mol% NaBH4 THF-MeOH (9:1) 

O 

OEt 

31 

30 °C, 1 h 

32 

TOF = 4580 h -1 

Scheme 16. Reduction of α,β-unsaturated ester catalyzed by iron porphyrin 30. 

More recently, the group of Chirik have shown elegantly the application of low valent iron 

complexes in the hydrogenation of various C-C double and C-C triple bounds. 34 Based on the 

mentioned work of Wrighton et al. an approach to stabilized 14 electron L3Fe(0) fragments 

was presented. The catalyst precursors were synthesized by reduction of dihalogen complexes 

33 containing a tridentate pyridinediimine ligand with sodium amalgam or with sodium 

triethylborohydride under an atmosphere of nitrogen (Scheme 17). The obtained bisdinitrogen 

complexes 34 are relative labile compounds and a loss of one equivalent of 

dinitrogen in solution at room temperature or an easy exchange against hydrogen or alkynes 

occurred. The catalyst activity was studied in the field of C-C double and C-C triple bond 

hydrogenation. Applying 0.3 mol% of the iron catalyst simple olefins such as 1-hexene or 

cyclohexene were hydrogenated with high turnover frequencies up to 1814 mol/h under 

comparatively mild reaction conditions (4 atm of hydrogen pressure and room temperature). 

The reaction was also carried out under preferred solvent-free conditions in neat substrates 

and leading to comparable activity. The scope and limitation of the catalyst system was 

demonstrated in the hydrogenation of various olefin units enclosing geminal, internal and 

trisubstituted olefins and furthermore diolefins. In the course of this it was ascertained that 

best activity was attained for terminal olefins > internal olefins = geminal olefins > 

trisubstituted olefins. In addition, one example of a functionalized olefin was mentioned. 

However, only a diminished activity was observed for dimethyl itaconate, albeit using higher 

catalyst loadings. In the case of cyclohexene some detailed investigations emphasized a 

deactivation of the catalyst by arene complexation either from the solvent or the aryl groups in 

the ligand. 35 Noteworthy, when comparing activity of catalyst 34 (1814 mol/h) with common 

catalysts e.g. Pd/C (TOF = 366 mol/h), RhCl(PPh3)3 (10 mol/h) or [Ir(cod)(PCy3)(py)]PF6 (75 

mol/h) in the hydrogenation of 1-hexene under optimized conditions a significant higher value 

was reached with the iron catalyst. 

50

R 1 

35 

R 2 


Ar 

N 

N 

Fe 

N 

Ar 

0.3 mol% 34 

H 2 (4 atm) 

X X 

33a = Cl 

33b = Br 


R 1 

36 

method A 

N 2 (1 atm), Na(Hg), pentane 

method B 

N 2(1 atm), NaBEt 3H, toluene 

R 2 

Ar 

N 

N 

Fe 

N 

Ar 

N 2 

36a: R 1 = C 6H 5; R 2 = H: TOF = 1344 mol/h 

36b: R 1 = C 6H 5; R 2 =CH 3: TOF = 104 mol/h 

36c: R 1 = n-Bu; R 2 = H: TOF = 1814 mol/h 

36d: R 1 =CH 2=CH(CH 2) 2; R 2 = H: TOF = 363 mol/h 

36e: R 1 = -COOCH 3; R 2 = CH 2COOMe: TOF = 3 mol/h 

37: cylohexene: TOF = 57 mol/h 

34 

N 2 

Ar = 2,6-( i Pr) 2C 6H 3 

Scheme 17. Preparation of catalyst precursors containing tridentate nitrogen ligands and 

abilities in catalytic reaction according to Chirik and co-workers. 

Further on the group of Chirik studied the influence of replacing the imino functionalities in 

ligand system 34 by phosphino groups (Scheme 18). 36 A different coordination mode was 

found since only one nitrogen ligand was replaced by hydrogen. The unstable complex 38 was 

also tested in the hydrogenation of 1-hexene, but no improvement of activity was observed. 

N 

H 

P i Pr 2 

Fe 

N 2 

P i Pr 2 

H 

38 

35c 

0.3 mol% 37 

H 2 (4 atm) 

pentane, 23 °C, 3 h 

Scheme 18. Application of iron aminodiphosphine complexes in hydrogenation reaction. 

36c 

51 

conv.: 98% 

Using the same synthetic method as described for catalyst 34 also diime complexes 39 were 

attainable (Scheme 19). 37 Due to the instability of dinitrogen complexes stabilization was 

carried out by introducing more suitable ligands e.g. alkynes, olefins or diolefins. However, in 

the hydrogenation of 1-hexene under comparable conditions only low activities were 

observed. Apart from synthesis and application of low valent iron complexes Chirik et al. 

carried out some mechanistic investigations. The suggestion of the catalytic cycle is presented 

in Scheme 20. Initially, an unsaturated iron complex is formed by expulsion of both 

dinitrogen molecules.


Ar 

N 

Fe 

N 

Ar 

L 

39 

35c 

0.3 mol% 39 

H 2 (4 atm) 

pentane, 22 °C, 3 h 

39a: Ar = 2,6-( i Pr) 2C 6H 3; L = (Me 3Si) 2C 2 TOF = 4 mol/h 

39b: Ar = 2,6-( i Pr) 2C 6H 3; L = cod TOF = 90 mol/h 

39c: Ar = 2,6-( i Pr) 2C 6H 3; L = coe TOF = 90 mol/h 

Scheme 19. Hydrogenation with low valent iron complexes. (cod = 1,5-cyclooctadiene, coe = 

cyclooctene). 

Next coordination of olefin takes place, which is preferred since also activation of hydrogen is 

feasible. After olefin coordination oxidative addition of hydrogen yields a formally 18 

electron complex. Insertion of the olefin obtained an alkyl complex, which recreate the 

starting complex via reductive elimination. Notably, the olefin complex also supports an 

isomerization of the double bond; hence an extension of possible intermediates is conceivable. 

H 

[Fe] 

R 

R 

[Fe](N 2) 2 

[Fe] 

-2N 2 

Scheme 20. Mechanism for the hydrogenation process proposed by Chirik et al. 

[Fe] 

3.4. Hydrogenation of imines and similar compounds 

H 

R 

Until today only a scarce number of hydrogenations of unsaturated CN functionalities have 

been described utilizing iron catalysts. On the one hand hydrogenation of N- 

H 

[Fe] 

R 

H 2 

R 

36c 

52


benzylideneaniline to yield N-benzylaniline was carried out by Markó et al. in presence of 

catalytic amounts of [NEt3H][HFe(CO)4], which was also applied for ketones/aldehydes 

reduction (vide supra). 38 Even if good to excellent activities were obtained in various 

solvents, for proceeding the reaction harsh conditions are required (150 °C, 100 bar). On the 

other hand Kaesz and co-workers reported the reduction of nitrogen heterocycles under water- 

gas shift conditions. 39 As catalyst Fe(CO)5 was used under high temperature and pressure. 

Moderate turnover numbers in the range of 18–37 were obtained. In the case of isoquinoline 

42 as main product the formylated compound 43 is observed. 

N 

1.8 mol% Fe(CO) 5, KOH 

H 2O, MeOH 

CO (500 psi), 150 °C, 15 h 

N 

H 

N 

1.8 mol% Fe(CO) 5, KOH 

H 2O, MeOH 

CO (500 psi), 150 °C, 15 h 

40 41 42 43 

Scheme 21. Hydrogenation of aromatic nitrogen heterocycles. 

3.5. Catalytic hydrosilylations 

In addition to catalytic reductions with molecular hydrogen or hydrogen donors also silanes 

represent useful reducing agents. 40 

Most examples in literature for hydrosilylation with iron complexes as catalyst are known for 

Fe(CO)5 or related iron carbonyl compounds. 41 The first use of iron pentacarbonyl was 

reported for the reaction of silicon hydrides with olefins at 100–140 °C to form saturated and 

unsaturated silanes according to Scheme 22. 42,43 

R 3SiH + RCH=CH 2 

R = Cl, OC 2H 5, C 2H 5 

Fe(CO) 5 

neat, 100-140 °C 

Scheme 22. Fe-catalyzed hydrosilylation of C-C double bonds. 

R 3SiCH 2CH 2R 

44 

R 3SiCH=CHR + H 2 

An excess of olefin favours the formation of the unsaturated product 44 while the silylated 

compound 45 dominated at higher ratio of silane to alkene. The described reaction was also 

carried out in the presence of colloidal iron and lead to results similar to those obtained with 

Fe(CO)5. Hydrosilylation of vinyltrimethylsilane 46 with chlorosilanes R3SiH using the 

modified iron carbonyl complex (CH2=CHSiMe3)Fe(CO)4 44,45 gave a mixture of α- and β- 

45 

N 

53 

O


isomers of the silylated product 47 and the unsaturated product 48 attained by 

dehydrogenative silylation (Scheme 23). 

R 3SiH + Me 3SiCH=CH 2 

46 

2.5-5 mol% 

(CH 2=CHSiMe 3)Fe(CO) 4 

neat, 70-80 °C, 3-4 h 

Scheme 23. Hydrosilylation of vinyltrimethylsilane 46. 

CH 3 

Me3SiCHSiR3 α-47 

+ Me3SiCH2CH2SiR3 β-47 

Me 3SiCH=CHSiR 3 + EtSiMe 3 

The ratio of formed compounds α-47, β-47 and 48 depends on the nature of the used 

hydrosilane R3SiH. There exists an indirect relationship between the yield of the unsaturated 

silane 48 and the catalytic activity of R3SiH (Cl3SiH > Cl2MeSiH > ClMe2SiH > Me3SiH). 

With exception of Me3SiH the α-isomer is mainly formed in all studied reactions. Iron 

pentacarbonyl is known to hydrosilylate functionalized olefins (Scheme 24). 46 For instance 

hydrosilylation of acrolein 49 with Et3SiH gave up to 95% of a mixture of cis- and trans- 

MeCH=CHOSiEt3 50 while acrolein diethyl acetal 51 forms the Markovnikov product 

Et3SiCH2CH2CH(OEt)2 52 and Et3SiOEt via C-O bond cleavage. Allylic alcohol reacts in the 

presence of Fe(CO)5 to give CH2=CHCH2OSiEt3 54 and propylOSiEt3 55. 

CH2=CHCHO + Et3SiH 49 

CH 2=CHCH(OEt) 2 + Et 3SiH 

51 

CH 2=CHCH 2OH + Et 3SiH 

53 

1-4 mol% Fe(CO) 5 

neat, 140 °C, 4 h 


neat, 140 °C, 4 h 


neat, 140 °C, 4 h 

Scheme 24. Hydrosilylation of functionalized olefins. 

48 

CH 3CH=CHOSiEt 3 

50 

Et3SiCH2CH2CH(OEt) 2 

52 

CH2=CHCH2OSiEt3 + CH3(CH2) 2OSiEt3 54 

55 

In 1993 the group of Murai has examined the effectiveness of the iron-triad carbonyl 

complexes, Fe(CO)5, Fe2(CO)9, Fe3(CO)12, as catalysts for the reaction of styrene with 

triethylsilane. 47 While Fe(CO)5 showed no catalytic activity Fe2(CO)9, and Fe3(CO)12 form 

selectively β-silylstyrene and ethylbenzene. Interestingly, Fe3(CO)12 is the catalyst that 

exhibited the highest selectivity. This trinuclear iron carbonyl catalyst was also successful 

54


applied for the reaction of different p-substituted styrenes with Et3SiH giving only the (E)-β- 

triethylstyrenes in 66–70% yield. 

R 

56 

+ Et3SiH 0.3 or 0.7 mol% 

Fe2(CO) 9 or Fe3(CO) 12 

SiEt3 + 

benzene, 40-80 °C, 

24-72 h 

R R 

57a: R = H; yield: 36-89% 

57b: R = CH3; yield: 67% 

57c: R = Cl; yield: 66% 

57a: R = OCH3; yield: 70% 

Scheme 25. Hydrosilylation of styrene derivatives. 

Hydrosilylation reactions catalyzed by iron carbonyl compounds often occur under drastic 

thermal conditions. Wrighton et al. have reported a photocatalyzed reaction of trialkylsilanes 

with alkenes in the presence of Fe(CO)5 at low temperature (0–50 °C). 48 It is well known that 

irradiation of mononuclear metal carbonyls leads to efficient dissociative loss of CO to yield 

coordinative unsaturated, 16-electron, intermediates (Scheme 26). 26 

Fe(CO) 5 

H 

R3Si H 

R3Si + HSiR 3 

hv 

Fe(CO) 4 

Fe(CO) 3 

-CO 

+ CO 

+ 

Fe(CO) 4 

- HSiR 3 

- + HSiR 3 

Fe(CO) 4 

hv hv 

H 

R3Si Fe(CO) 3 

+ 

Fe(CO) 3 + CO 

Scheme 26. Formation of the catalytic active species by irradiation. 

Irradiation of Fe(CO)5 in the presence of trialkylsilane R3SiH and alkene initially yields a 

mixture of Fe(CO)4(alkene) and (H)(SiR3)Fe(CO)4 which were determined by infrared 

spectroscopy. (H)(SiR3)Fe(CO)3(alkene) is postulated to be the catalytic active species 

58 

55


photogenerated from these intermediates according to Scheme 26. Continuous irradiation is 

needed to maintain a steady-state concentration of the repeating unit “Fe(CO)3”. Such an iron 

tricarbonyl complex was also detected by infrared spectroscopy in the photoinduced addition 

of R3SiH to 1,3-butadiene with Fe(CO)5. 49 Polymer-anchored ironcarbonyl species were 

described to catalyze the hydrosilylation of 1-pentene with HSiEt3 to give a mixture of pentyl- 

and pentenylsilanes. 50 The different pathways of the mechanism of transition metal-catalyzed 

hydrosilylation are summarized in Scheme 27. A commonly proposed mechanism involves 

the insertion of the olefin into the Fe-H bond of complex (H)(SiR3)Fe(CO)3(alkene) followed 

by reductive elimination of the alkyl and the silyl group to form an alkylsilane (pathway B). 

In an alternative mechanism insertion of the olefin into the Fe-Si bond of complex 

(H)(SiR3)Fe(CO)3(alkene) is discussed (pathway A). This route which is also suggested for 

the use of Fe3(CO)12 explains the formation of vinylsilanes as by-product in 

ydrosilylations. 51 

h 

H 

H 

H 

Fe(CO) 3 

+ HSiR 3 

C 

SiR 3 

Fe(CO) 3 

SiR 3 

SiR 3 

+ 

H 

H 

A 

R 3Si 

Fe(CO) 3 

H 

R 3Si 

+ HSiR 3 

H 

Fe(CO) 3 

Fe(CO) 3 

B 

+ HSiR 3 

R 3Si 

R 3Si 

Fe(CO) 3 

Scheme 27. Proposed catalytic cycle for the hydrosilylation of olefins in the presence of 

Fe(CO)5. 

56


The photoinduced alkene insertion into the Fe-Si bond of (η 5 -C5Me5)Fe(CO)R was shown to 

be reversible (reaction C). 52 A reactivity study of complex (H)Fe(CO)4SiPh3 with 

nucleophiles allowed a better understanding of the underlying reaction processes. 53 Under 

photochemical conditions the activation or the substitution of the carbonyl ligands supports 

the classical mechanism involving insertion of the coordinated olefin in the Fe-Si (A) or the 

Fe-H (B) bonds. Under thermal conditions, however, a direct addition of the Fe-H group by a 

radical or ionic process can occur as observed in the reaction of (H)Fe(CO)4SiPh3 with 

isoprene. These mechanistic investigations for photo-generated hydrosilylation have been 

transmitted to the reaction of the iron carbonyl complex (CH2=CHSiMe3)Fe(CO)4 with 

vinylsilane and R3SiH. 45 Tetrahedral heterometallic clusters containing iron have proven to be 

suitable catalysts in the photoinitiated hydrosilylation of acetophenone with triethylsilane. 54 

Although a chiral FeCoMoS tetrahedron was used only racemic product and racemic cluster 

have been isolated. This fact can be explained by photo-racemization of the chiral catalyst 

which proceeds faster than hydrosilylation reaction. Instead of irradiation metal vapour 

generation at -196 °C was described as activation method for transition metal catalysts. 55 Iron 

vapour co-condensed with isoprene catalyzed the hydrosilylation with triethoxysilane. Not 

surprisingly exclusive 1,4-addition is observed. 

The group of Brunner investigated the influence of thermal or photoinduced activation of 

Fe(Cp)(CO) complexes in the hydrosilylation of acetophenone 4b with diphenylsilane 

forming quantitatively the silylated 1-phenylethanol 59 (Scheme 28). 56,57 

O 

4b 

+ Ph 2SiH 2 

0.3 mol% 65: 

neat, 23 h, hv 

0.5-1 mol% 62, 63, 64: 

neat, 50-80 °C, 24 h 

OSiHPh 2 

59 

OSiHPh 2 

60 

Cp` 

Cp` 

Fe 

Fe 

CO 

L 

CH3 61 

CO 

L 

C 

O 

62 

Cp` 

Fe Cp(OC)Fe 

CO 

OC 

CH3 63 

Scheme 28. Asymmetric hydrosilylation with chiral iron complexes. 

H 

Men 2 

P 

64 

CH 3 

Men = Menthyl 

Fe CO 

The absence of silyl enol ether 60 can be explained by a hydrosilylation mechanism involving 

a Fe-Si-H three-centre bond rather than a Fe-H species. Although optically active ligands of 

type 61, 62 and 63 containing chiral iron atoms were used, only poor enantioselectivities 

below 10% ee have been achieved (L = DIOP [O-isopropyliden-2,3-dihydroxy-1,4- 

57


bis(diphenylphosphino)butane]). 58 The rate determining step in this reaction is the thermal 

loss of the phosphine ligand L in 61 and 62 and methyl migration in 63, followed by addition 

of phenylsilane and subsequent reaction with acetophenone. Under photo-irradiation 

conditions hydrosilylation occured very fast with complex 64 as catalyst producing the 

silylated (S)-1-phenylethanol 59 in 33% ee. This was the first appreciable example for an 

enantioselective iron-catalyzed hydrosilylation of ketones. Very recently, Nishiyama et al. 

pursued a different elegant strategy to find an efficient catalytic system based on iron. 59 They 

combined Fe(OAc)2 and multi-nitrogen-based ligand such as N,N,N´,N´- 

tetramethylethylendiamine (tmeda), bis-tert-butyl-bipyridine (bipy-tb), or 

bis(oxazolinyl)pyridine (pybox) to catalyze the hydrosilylation of ketones to give the 

corresponding alcohol after acidic cleavage of the silyl ether (Scheme 29). The reaction was 

carried out under mild condition (THF at 65 °C, 24 hours) producing yields up to 95%. Using 

tmeda as nitrogen ligand hydrosilylation works also with other aromatic ketones. 

R 

OH 

5b: R = H yield: 93% 

5o: R = 4-MeO yield: 94% 

5t: R = 4-PhO yield: 90% 

OH 

5w: yield: 62% 

MeO 

OH OH 

OMe 

5p: yield: 94% 5u: yield: 72% 

OH 

5x: yield: 91% 

OH 

n-C 5H 11 

5y: yield: 94% 

5v: yield: 94% 

OH 

OH 

5k: yield: 89% 

Scheme 29. Substrate cope of the Fe-catalyzed hydrosilylation of ketones in the presence of 

tmeda. 

Ph 

5 mol% Fe(OAc) 2 

O nitrogene ligand 

OH 

(EtO) 2MeSiH 

* 

65 

THF, 65 °C, work 

up with H 3O + 

Ph 

66 

Bn 

O 

N 

N 

pybox-bn 

67 

N 

O 

Bn 

O 

N 

H 

N N 

R R 

58 

O 

68: R = i-Pr bopa-ip 

69: R = t-Bu bopa-tb 

Scheme 30. Asymmetric hydrosilylation of ketone 65 with iron catalysts according to 

Nishiyama and co-workers.


The application of chiral tridentate nitrogen ligands leads to the enantioselective reduction of 

methyl 4-phenylphenylketone 65. While pybox-bn 67 gives 37% ee of 66, bopa-ip 68 and tb 

69 increased the enantioselectivity up to 57% ee and 79% ee, respectively. Recent results 

from our group revealed that it is possible to perform Fe-catalyzed hydrosilylations of 

acetophenone also in the presence of chiral phosphine ligands. Here enantioselectivities up to 

80% ee have been achieved. 60 

Iron-catalyzed hydrosilylations of olefins in the presence of nitrogen ligands were first 

realized by Chirik et al. 34,35 They investigated the reaction of 1-hexene with PhSiH3 or Ph3SiH 

in the presence of iron catalyst 34 containing a tridentate pyridinediimine ligand (Scheme 17) 

which produce hydrosilylation over a course of minutes at ambient temperature. In both cases, 

the anti-Markovnikov product was formed exclusively. On the basis of these results a series of 

olefins (see Scheme 17) was examined. Terminal alkenes such as 1-hexene and styrene react 

most rapidly followed by gem-disubstituted olefins and internal olefins. The silylation of 

alkynes was also examined and proceeds efficiently under mild conditions to the 

corresponding silylalkene. 

3.6. Concluding Remarks 

Since the beginning of transition metal catalyzed hydrogenations and hydrosilylations more 

than 40 years ago a tremendous number of studies were directed to develop powerful methods 

for organic synthesis. In the past Rh, Ir and Ru clearly constitute the metals of choice for such 

transformations. Several hundreds of catalysts are nowadays commercially available for 

chemists around the world. However, the accelerated costs and the stronger requirements for 

pharmaceuticals cast a shadow on these commonly used transition metals. 

For the mid-term future we expect an increased use of more available and “biomimetic” 

metals. Clearly, iron is an ideal example for this. Unfortunately simple method transfer from 

Rh, Ir and Ru to Fe is not readily possible. So far iron based hydrogenations and 

hydrosilylations are far off to be general methods for organic chemistry. Typically 

comparably high catalyst loadings and harsh reaction conditions are required. In order to 

allow for more synthetic applications especially more functional group tolerance and also 

efficient control of stereoselectivity is needed. There are some promising developments like 

the recent work of Chirik and Nishiyama who demonstrates that these goals can be achieved. 

It will be interesting to take part in this renaissance of iron chemistry. 

59



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64


4. Objectives of the work 

4.1. Application of monodentate phosphine ligands in asymmetric hydrogenations 

Since earlier works have proven an excellent behaviour of ligands containing 4,5–dihydro– 

3H–dinaphtho[2,1–c;1´,2´–e]phosphepine scaffold in the asymmetric hydrogenation of α– 

amino acid precursors, itaconic acid derivatives and β–ketoesters, we focused our attention on 

extension of scope and limitation of this ligand tool box. Several challenging substrate 

classes, based on unsaturated C-C bonds, were synthesized and subjected to catalytic 

reduction. 

4.1.1. Asymmetric hydrogenation of N–acyl enamides 

Until the end of 2004 only two reports were published dealing with the rhodium–catalyzed 

hydrogenation of N–acyl enamides in the presence of monodentate phosphines. On the one 

hand the utilization of chiral phospholanes by Fiaud and co–workers, which attained good 

enantioselectivities up to 73% ee, when (Z)–N–(1–phenylprop–1–enyl)acetamide was 

hydrogenated. 1 On the other hand, Reetz et al. described the rhodium–catalyzed 

hydrogenation of N–(1–phenylvinyl)–acetamide with ligands based on 4,5–dihydro–3H– 

dinaphtho[2,1–c;1´,2´–e]phosphepine (vide supra). 2 Surprisingly, the tert–butyl–substituted 

ligand showed better selectivity and yield than the phenyl–substituted ligand, which is in 

contrast to other benchmark tests such as the asymmetric hydrogenation of α–amino acid 

precursors, dimethyl itaconate and β–ketoesters where always the opposite behaviour was 

observed. The interesting results of Reetz and co–workers stimulated us to study the potential 

of our ligand library in the field of asymmetric hydrogenation of N–acyl enamides in more 

detail. 

4.1.2. Asymmetric hydrogenation of β–dehydroamino acid derivatives 

Since, β–amino acids are interesting building blocks for the synthesis of biologically active 

compounds the synthesis via asymmetric hydrogenation of unsaturated precursors offers a 

versatile and powerful approach. Currently bidentate phosphorous ligands have been proven 

to be effective in the asymmetric hydrogenation of β–dehydroamino acid derivatives with 

enantioselectivities up >99% ee, while a monodentate version is so far scarcely reported. Here 

only the group of Börner accounted enantioselectivities up to 93% ee with monodentate


phospholane ligand. 3 We became interested in studying the behaviour of chiral monodentate 

44,5–dihydro–3H–dinaphtho[2,1–c;1´,2´–e]phosphepine in the rhodium–catalyzed 

asymmetric hydrogenation of various β–dehydroamino acid derivatives to give optically 

active β–amino acids. 

4.1.3. Asymmetric hydrogenation of enol carbamates 

Pioneering work in the field of enantioselective hydrogenation of enol carbamates, which are 

suitable precursors for chiral alcohols, has been reported by Feringa, de Vries, Minnaard and 

co–workers applying rhodium–catalysts containing monodentate phosphoramidites 

(MonoPhos–family) and obtaining enantioselectivities up to 98% ee. 4 However, until today 

no additional studies on the reduction of enol carbamates were reported. Hence, we became 

interested in testing our ligand library in this purpose. 

4.2. Transfer hydrogenation 

4.2.1. Homogeneous iron catalyst in reduction chemistry 

With regard to future catalyst developments a fundamental challenge will be the 

substitution of expensive and rare transition metals by inexpensive and abundantly available 

metals such as iron. So far, homogeneous iron catalysts have been most frequently applied for 

carbon–carbon coupling reactions, such as olefin polymerizations, cross couplings, and 

cycloadditions. However, much less attention was directed towards iron–catalyzed (transfer) 

hydrogenations, albeit the relevance of such reductions is evident even with respect to 

industrial applications. Until today only a few number of research groups reported the 

application of iron salts and iron complexes in the reduction of α,β–unsaturated carbonyl 

compounds and ketones using a transfer hydrogenation protocol. 5 For tuning the activity and 

selectivity of these catalysts oxygen and moisture sensitive tetradentate phosphines or 

aminophosphines have been predominantly applied as ligands. Our goal was to develop a 

practical iron hydrogenation catalyst system, which should be easily prepared and highly 

tuneable. Thus, the use of commercially available iron complexes in combination with two 

different ligands (phosphines and amines) instead of tetradentate ligands seemed to be a 

useful approach. Furthermore inspired by nature we thought that multidentate nitrogen ligands 

should be also suitable ligands for stabilizing iron as metal center in transfer hydrogenations. 

The influence of different reaction parameters on the catalytic activity will be investigated in


the transfer hydrogenation of aliphatic and aromatic ketones utilizing 2–propanol as hydrogen 

donor in the presence of base. 

4.2.2. Transfer hydrogenation of ketones with ruthenium catalysts 

4.2.2.1. Transfer hydrogenation with ruthenium carbene catalysts 

With regard to transfer hydrogenations different carbene or carbene-phosphine–systems 

containing Rh, Ir, Ru or Ni have been reported. Excellent turnover frequencies up to 120000 

h -1 were reported by the groups of Baratta and Herrmann applying a ruthenium–carbene– 

phosphine–catalyst. 6 However, for reduction of a typical substrate, e.g. acetophenone, with 

phosphine–free ruthenium–carbene catalysts lower turnover frequencies (TOF 333 h -1 ) 7 were 

achieved in comparison to iridium (500 h -1 ) 8 and rhodium systems (583 h -1 ). 9 Due to the 

economical benefit of ruthenium metal compared to rhodium or iridium and the advantages of 

phosphine–free systems, it will be an important goal to search for more active ruthenium 

carbene catalysts. 

4.2.2.2. Asymmetric transfer hydrogenation with ruthenium catalysts 

Significantly less is known of the transfer of chiral information for tridentate ligands, while 

transfer hydrogenation is dominated by highly active bidentate systems. 10 Up to now only a 

limited number of auspicious tridentate nitrogen-containing N,N,N–ligands were established. 

For example (R)–phenyl–ambox and different pyridinebisoxazoline (pybox) ligands have 

been applied for the reduction of acetophenone. More recently, a new class of chiral tridentate 

amines so called pybim (parent structure: 2,6-bis–([4R,5R]–4,5–diphenyl–4,5–dihydro–1H– 

imidazol–2-yl)–pyridine) for the ruthenium–catalyzed epoxidations was introduced by Beller 

et al. 11 The resemblance between pybim and pybox stimulated our research to study the 

potential of this class of ligands in the transfer hydrogenation of aromatic and aliphatic 

ketones.



1 C. Dobrota, M. Toffano, J.-C. Fiaud, Tetrahedron Lett. 2004, 45, 8153–8156. 

2 M. T. Reetz, G. Mehler, A. Meiswinkel, Tetrahedron: Asymmetry 2004, 15, 2165–2167. 

3 V. Bilenko, A. Spannenberg, W. Baumann, I. Komarov, A. Börner, Tetrahedron: 

Asymmetry 2006, 17, 2082–2087. 

4 a) X. Jiang, M. van den Berg, A. J. Minnaard, B. Feringa, J. G. de Vries, Tetrahedron: 

Asymmetry 2004, 15, 2223–2229; b) L. Panella, B. L. Feringa, J. G. de Vries, A. J. 

Minnaard, Org. Lett. 2005, 7, 4177–4180. 

5 a) K. Jothimony, S. Vancheesan, J. Mol. Catal. 1989, 52, 301–304; b) K. Jothimony, S. 

Vancheesan, J. C. Kuriacose, J. Mol. Catal. 1985, 32, 11–16; c) J.-S. Chen, L.-L. Chen, 

Y. Xing, G. Chen, W.-Y. Shen, Z.-R. Dong, Y.-Y. Li, J.-X. Gao, Huaxue Xuebao 2004, 

62, 1745–1750; d) C. Bianchini, E. Farnetti, M. Graziani, M. Peruzzini, A. Polo, 


6 W. Baratta, J. Schütz, E. Herdtweck, W. A. Herrmann, P. Rigo, J. Organomet. Chem. 

2005, 690, 5570–5575. 

7 A. A. Danopoulos, S. Winston, W. B. Motherwell, Chem. Commun. 2002, 1376–1377. 

8 M. Albrecht, J. R. Miecznikowski, A. Samuel, J. W. Faller, R. H. Crabtree, 


9 M. Poyatos, E. Mas-Marzá, J. A. Mata, M. Sanaú, E. Peris, Eur. J. Inorg. Chem. 2003, 

1215–1221. 

10 a) Y. Jiang, Q. Jiang, X. Zhang, J. Am. Chem. Soc. 1998, 120, 3817–3818; b) D. 

Cuervo, M. P. Gamasa, J. Gimeno, Chem. Eur. J. 2004, 10, 425–432. 

11 a) S. Bhor, G. Anilkumar, M. K. Tse, M. Klawonn, C. Döbler, B. Bitterlich, A. 

Grotevendt, M. Beller, Org. Lett. 2005, 7, 3393–3396; b) G. Anilkumar, S. Bhor, M. K. 

Tse, M. Klawonn, B. Bitterlich, M. Beller, Tetrahedron: Asymmetry 2005, 16, 3536– 

3561.

5. Application of monodentate phosphine ligands in asymmetric hydrogenation 69 

5.1. Enantioselective rhodium–catalyzed hydrogenation of enamides in 

the presence of chiral monodentate phosphines 

Stephan Enthaler, Bernhard Hagemann, Kathrin Junge, Giulia Erre, and Matthias 

Beller*, Eur. J. Org. Chem. 2006, 2912–2917. 

Contributions 

Ligands 5c and 5f were synthesized by Dr. B. Hagemann. Furthermore, the asymmetric 

hydrogenation of substrate 6f and the combinatorial ligand approach (Table 3) were carried by 

Dr. B. Hagemann.

FULL PAPER 

DOI: 10.1002/ejoc.200600024 

Enantioselective Rhodium-Catalyzed Hydrogenation of Enamides in the 

Presence of Chiral Monodentate Phosphanes 

Stephan Enthaler, [a] Bernhard Hagemann, [a] Kathrin Junge, [a] Giulia Erre, [a] and 

Matthias Beller* [a] 

Keywords: Asymmetric catalysis / Homogeneous catalysis / Hydrogenation / Monodentate phosphane ligands / Enamides 

The rhodium-catalyzed asymmetric hydrogenation of different 

acyclic and cyclic N-acyl enamides to give N-acyl-protected 

optically active amines has been examined for the first 

time in detail in the presence of chiral monodentate 4,5-dihydro-3H-dinaphthophosphepines 

5a–i. The enantioselectivity 

is largely dependent on the nature of the substituent at the 

Introduction 

The importance of chiral amines is demonstrated by their 

broad scope of applications as building blocks and synthons 

for pharmaceuticals and agrochemicals. In addition, 

they are of significant use for the synthesis of natural compounds, 

chiral auxiliaries, and optically active ligands. [1] 

Hence, the development of new and improved methods for 

the preparation of enantiomerically pure amines is an important 

target of industrial and academic research. Several 

synthetic approaches to optically active amines have been 

established in the past. Still one of the most practical approaches 

is the separation of enantiomers through resolution, 

e.g. in the presence of chiral acids. The main drawback 

of this concept is the poor atom efficiency and the negative 

environmental impact. A more attractive access is represented 

by applying enantiomerically pure starting materials 

from the “chiral pool”. Another powerful strategy is the 

application of stereoselective syntheses in particular reactions 

catalyzed by transition-metal complexes. [2] Examples 

of such transition-metal-catalyzed reactions, which offer a 

versatile and elegant approach to enantiomerically pure 

amines, are the alkylation or arylation of imines, hydrocyanation 

of carbon–carbon double bonds and aziridination. 

[2c] However, the most popular catalytic reaction with 

respect to industrial applications is the asymmetric hydrogenation 

of imines or N-protected enamines and enamides. 

[3] 

Pioneering work in the field of enantioselective hydrogenation 

of enamides has been reported by Kagan and co- 

[a] Leibniz-Institut für Katalyse an der Universität Rostock e.V., 

Albert-Einstein-Str. 29A, 18059 Rostock, Germany 

Fax: +49-381-12815000 

E-mail: matthias.beller@ifok-rostock.de 

2912 

phosphorus atom and the enamide substrate. Applying optimized 

conditions up to 95% ee and catalyst activity up to 

2000 h –1 (TOF) have been achieved. 

(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, 

Germany, 2006) 

workers. Applying diphosphane rhodium catalysts enantioselectivity 

up to 90% has been obtained. [4] Over a period of 

nearly 30 years the development of new ligands for asymmetric 

hydrogenation has focused on the synthesis of bidentate 

ligands. During this time several effective bidentate 

phosphanes such as Me-DuPhos, Me-BPE, DIOP, BINAP 

and others were developed for the hydrogenation of enamides. 

[4,5] At the end of the 20 th century the predominant 

role of bidentate ligands changed and monodentate ligands 

received more attention. [6,7] The advantages of monodentate 

phosphorus ligands are their easier synthesis and 

tunability compared to bidentate phosphanes. Scheme 1 illustrates 

some examples of monodentate phosphorus ligands 

for asymmetric hydrogenation on the basis of the chiral 

1,1�-binaphthol skeleton. Important contributions in 

this area came independently from Feringa and de Vries et 

al. [8] (phosphoramidites 1), Reetz et al. [9] (phosphites 2), 

and Pringle and Claver et al. [10] (phosphonites 3). Furthermore, 

excellent enantioselectivity was shown by Zhou and 

co-workers applying monodentate spiro phosphoramidites 

(SIPHOS). [11] 

Following the original work of Gladiali [12] and parallel 

to Zhang, [13] we have established the synthesis of various 

monodentate phosphanes based on a 4,5-dihydro-3H-dinaphtho[2,1-c;1�,2�-e]phosphepine 

framework (4 and 5a–i), 

which resembles the 1,1�-binaphthol core. [14] Recently, we 

have shown that asymmetric hydrogenation of amino acid 

precursors, dimethyl itaconate and β-keto esters proceeds 

with enantioselectivities up to 95% ee in the presence of 

ligand 5a. [13] Moreover, other groups demonstrated the usefulness 

of these ligands in several catalytic asymmetric reactions. 

[15] 

To the best of our knowledge there exists only one publication 

dealing with the hydrogenation of enamides in the 

© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2006, 2912–2917

Enantioselective Hydrogenation of Enamides in the Presence of Phosphanes FULL PAPER 

Scheme 1. Chiral monodentate ligands with 2,2�-binaphthyl framework. 

presence of monodentate phosphepines. Here, Reetz et 

al. [16] described the rhodium-catalyzed hydrogenation of N- 

(1-phenylvinyl)acetamide (6a) with ligands 5a [conversion: 

50%; enantiomeric excess: 14% (R)] and 5i [conversion: 

94%; enantiomeric excess: 24% (R)] in dichloromethane. To 

our surprise the tert-butyl-substituted ligand 5i showed better 

selectivity and yield than the phenyl-substituted ligand 

5a. In our benchmark tests, for instance, in the asymmetric 

hydrogenation of amino acid precursors, dimethyl itaconate 

and β-keto esters, we always observed the opposite behaviour. 

Discussion 

The interesting results of Reetz and co-workers [15] stimulated 

us to study the potential of our ligand library 5a–i in 

the field of asymmetric hydrogenation of enamides in more 

detail. In general, the ligands are prepared by metallation of 

2,2�-dimethylbinaphthyl with two equiv. of n-butyllithium, 

followed by quenching with diethylamino(dichloro)phosphane. 

Deprotection with gaseous HCl produced 4-chloro- 

4,5-dihydro-3H-dinaphtho[2,1-c;1�,2�-e]phosphepine in a 

yield of 80%. This enantiomerically pure chlorophosphane 

is easily coupled with various Grignard reagents to give a 

broad selection of ligands of type 5. 

Unsubstituted and substituted N-(1-phenylvinyl)acetamides 

6a–6e were obtained by reacting the corresponding 

benzonitrile with a methyl Grignard followed by addition 

of acetic anhydride. [8e] The cyclic N-acyl enamide 6f was 

synthesized by a standard protocol implying transformation 

of the ketone to the corresponding oxime and subsequent 

reductive acylation with iron in the presence of acetic acid 

anhydride. [17] 

Initial studies on the influence of reaction conditions 

were carried out with N-(1-phenylvinyl)acetamide (6a) as 

substrate and 4-phenyl-4,5-dihydro-3H-dinaphtho[2,1c;1�,2�-e]phosphepine 

(5a) as our standard ligand. Typically, 

we used an in situ pre-catalytic mixture of 1 mol-% 

[Rh(cod) 2]BF 4 and 2.1 mol-% of the corresponding ligand. 

All hydrogenation reactions were carried out in an 8fold 

parallel reactor array with 3.0 mL reactor volume. [18] 

At first, we focused our attention on the influence of 

different solvents, such as dichloromethane, methanol, ethyl 

acetate, toluene, and also variation of the initial pressure 

(1.0 bar, 5.0 bar and 10 bar). Selected results are presented 

in Figure 1. 

Figure 1. Solvent and pressure variation. Reactions were carried 

outat30°C for 24 h with 0.0024 mmol [Rh(cod) 2]BF 4, 0.005 mmol 

ligand 5a and 0.24 mmol substrate in 2.0 mL solvent. Conversion 

and ee values were determined by GC [50 m Lipodex E (Macherey– 

Nagel), 80 °C, (R)-7a 26.7 min, (S)-7a 28.3 min]. The absolute configuration 

was determined by comparing the sign of specific rotation 

with reported data and the original sample (Aldrich). [5i] 

For all solvents best enantioselectivity (80–90% ee) is 

achieved at 1.0 bar, but without complete conversion within 

reasonable time (24 h). Increasing the pressure of hydrogen 

to 5.0 bar or 10.0 bar accelerated the reaction and full conversion 

is reached, but at somewhat lower selectivity. The 

results also indicated toluene as the solvent of choice for 

our model reaction (conversion: 96%; enantioselectivity: 

91%). 

To find the optimum of the enantioselectivity−pressure 

dependency we performed a fine tuning of the hydrogen 

pressure in toluene. At 2.5 bar hydrogen pressure both good 

enantioselectivity (93% ee) and acceptable reaction time 

(6 h) have been achieved. 

Next, we investigated the influence of the temperature on 

the selectivity and yield as described in Figure 2. Applying 

our model ligand 5a there is no pronounced effect on the 

selectivity between 10 and 30 °C. [19] At higher temperatures 

a decrease of the ee is observed (87% ee at 50 °C and 83% 

ee at 70 °C). 

Eur. J. Org. Chem. 2006, 2912–2917 © 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org 2913

FULL PAPER 

Figure 2. Dependency of enantioselectivity vs. temperature. Reactions 

were carried out at the corresponding temperature for 1–24 h 

with 0.0024 mmol [Rh(cod) 2]BF 4, 0.005 mmol ligand 5a and 

0.24 mmol substrate in 2.0 mL toluene. Conversion and ee values 

were determined by GC [50 m Lipodex E (Macherey–Nagel), 

80 °C, (R)-7a 26.7 min, (S)-7a 28.3 min]. [5i] 

To estimate the activity of the catalyst in more detail the 

ratio between metal and substrate was varied starting from 

initially 1:100 to 1:2000. At 50 °C and 2.5 bar of hydrogen 

complete conversion was observed within one hour, which 

corresponds to a turnover frequency (TOF) of 2000 h –1 . 

In order to evaluate the substituent effect at the phosphorus 

atom of the ligand, we studied the asymmetric hydrogenation 

of N-(1-phenylvinyl)acetamide (6a) in the presence 

of nine different 4,5-dihydro-3H-dinaphtho[2,1-c;1�,2�e]phosphepines 

(5a–5i) using the optimized reaction conditions 

(2.5 bar hydrogen pressure, toluene, 30 °C, 6 h). These 

results are presented in Table 1. 

In agreement with our previous studies, it appeared 

that for obtaining good enantioselectivity aryl-substituted 

phosphepine ligands are necessary, while alkyl-substituted 

ligands showed significantly lower selectivity. Substitution 

on the phenyl ring at the phosphorus atom with electronwithdrawing 

(5b, 5c) as well as electron-donating groups 

(5d–5g) resulted in decreased selectivity in comparison to 

the phenyl ligand 5a. Here, only ligand 5e represented an 

exception (Table 1, Entry 5), which led to 93% ee. 

Interestingly, the behaviour of the tert-butyl ligand 5i is 

quite different in the hydrogenation of 6a. In contrast to 

the results obtained by Reetz et al., under our reaction conditions 

compound 5i induced a change in the absolute configuration 

of the product to the opposite (S)-enantiomer, 

albeit with significantly lower ee. 

In addition to the ligands 5, we also tested the commercially 

available (S)-MonoPhos ligand (1, R 1 =R 2 = Me), 

which gives excellent enantioselectivity in various hydrogenations 

of prochiral double bonds. [8,20] However, in the present 

test reaction we obtained only poor yield and enantioselectivity 

(Table 1, Entry 10). 

2914 

S. Enthaler, B. Hagemann, K. Junge, G. Erre, M. Beller 

Table 1. Hydrogenation of N-(1-phenylvinyl)acetamide (6a). [a] 

Entry Ligand Conversion [%] [b] ee [%] [b,c] 

1 5a �99 93 (R) 

2 5b �99 72 (R) 

3 5c �99 88 (R) 

4 5d �99 87 (R) 

5 5e �99 93 (R) 

6 5f �99 63 (R) 

7 5g �99 90 (R) 

8 5h �99 30 (R) 

9 5i �99 16 (S) 

10 1 4 19 (S) 

[a] All reactions were carried out at 30 °C under 2.5 bar pressure 

of hydrogen for 6 h with 0.0024 mmol [Rh(cod) 2]BF 4, 0.005 mmol 

ligand and 0.24 mmol substrate in toluene (2.0 mL). [b] Conversion 

and ee values were determined by GC [50 m Lipodex E (Macherey– 

Nagel), 80 °C, (R)-7a 26.7 min, (S)-7a 28.3 min]. [c] The absolute 

configuration was determined by comparing the sign of specific 

rotation with reported data and the original sample (Aldrich). [5i] 

To demonstrate the scope and limitations of our ligand 

toolbox we performed the asymmetric hydrogenation of 

four different N-(1-phenylvinyl)acetamides (Table 2). Regarding 

the substrates both electron-donating substituents 

at the phenyl group, in particularly a methoxy group in 

para- as well as in meta-position and electron-withdrawing 

substituents such as para-fluoro or para-trifluoromethyl 

have been tested. Enantioselectivity up to 95% ee is obtained 

with ligands 5a (Table 2, Entry 1) and 5e (Table 2, 

Entry 5) for electron-rich substrates. In general, aryl phosphepines 

with electron-donating substituents showed better 

selectivity than phosphepines having electron-withdrawing 

groups. 

The introduction of electron-withdrawing substituents in 

N-(1-phenylvinyl)acetamide 6d and 6e decreased the 

enantioselectivity compared to the non-substituted N-(1phenylvinyl)acetamide 

(6a). Here, the best selectivities of 

83–86% ee are obtained with ligands 5a, 5e and 5g. 

Again for all substrates 6a–6e the alkyl-substituted 4,5dihydro-3H-dinaphtho[2,1-c;1�,2�-e]phosphepines 

gave significantly 

lower selectivity. 

Next, the hydrogenation of the sterically more hindered 

N-(3,4-dihydro-1-naphthyl)acetamide (6f) was tested 

(Scheme 2). The use of different pre-catalysts including 

[Rh(5a) 2(cod)]BF 4, [Rh(5e) 2(cod)]BF 4 and [Rh(5i) 2(cod)] 

BF 4 gave an excellent yield (�99%) of 7f. 

However, the observed enantioselectivity is significantly 

lower [5a: 15%(S); 5e: 11%(S); 5i: 35%(R)] when compared 

to 1,1-disubstituted enamides. These results indicate 

a crucial influence of the substitution pattern on the enamide 

group. 

It is important to note that in comparison to bidentate 

ligands the application of monodentate ligands offers an 

www.eurjoc.org © 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2006, 2912–2917


Table 2. Asymmetric hydrogenation of substituted N-(1-phenylvinyl)acetamides 

6b–6e. [a] 

7b 7c 

Entry Ligand (R 1 =CH 3O; R 2 =H) (R 1 =H;R 2 =CH 3O) 

ee [%] [b,c] ee [%] [b,d] 

1 5a 91 (R) 95 (R) 

2 5b 63 (R) 72 (R) 

3 5c 79 (R) 84 (R) 

4 5d 87 (R) 87 (R) 

5 5e 92 (R) 89 (R) 

6 5f 33 (R) 53 (R) 

7 5g 89 (R) 89 (R) 

8 5h rac 26 (R) 

9 5i 21 (S) 23 (S) 

Entry Ligand 7d (R 1 =F) 7e (R 1 =CF 3) 

ee [%] [b,c] ee [%] [b,c] 

10 5a 86 (R) 78 (R) 

11 5b 51 (R) 62 (R) 

12 5c 71 (R) 73 (R) 

13 5d 71 (R) 65 (R) 

14 5e 86 (R) 78 (R) 

15 5f 34 (R) 68 (R) 

16 5g 83 (R) 85 (R) 

17 5h 4(R) 44 (R) 

18 5i rac 25 (S) 



ligand and 0.24 mmol substrate in 2.0 mL toluene. [b] Conversion 

(�99 %) was determined by GC (Agilent Technologies, 30 m, 50– 

300 °C), ee values were determined by GC [50 m Lipodex E (Macherey–Nagel), 

100–180 °C, (R)-7b 36.1 min, (S)-7b 36.4 min, (R)-7c 

34.8 min, (S)-7c 35.0 min, (R)-7d 31.0 min, (S)-7d 31.2 min, (R)- 

7e 32.4 min, (S)-7e 32.7 min]. [c] The absolute configurations were 

determined by comparing the sign of specific rotation with reported 

data. [5i] [d] Absolute configuration of product was assigned 

by analogy. 

Scheme 2. Asymmetric hydrogenation of N-(3,4-dihydro-1-naphthyl)acetamide 

(6f). All reactions were carried out at 30 °C under 

2.5 bar pressure of hydrogen for 6 h with 0.0024 mmol [Rh(cod) 2]- 

BF 4, 0.005 mmol ligand and 0.24 mmol substrate in 2.0 mL toluene. 

Conversion was determined by GC (Agilent Technologies, 

30 m, 50–300 °C) and ee values were determined by HPLC [AD- 

H Chiralpak (Agilent Technologies), n-hexane/ethanol, 95:5, rate 

1.0 mL/min, (S)-7f 6.2 min, (R)-7f 7.2 min]. The absolute configuration 

was determined by comparing the sign of specific rotation 

with reported data. 

opportunity to replace one equiv. of the ligand by other chiral 

or achiral monodentate ligands. This remarkable combinatorial 

approach was introduced by Reetz et al., [9d–9f,15,21] 

and Feringa et al. [22] for different transition-metal-catalyzed 

reactions. [23] 

We followed this concept and used 4-phenyl-4,5-dihydro- 

3H-dinaphtho[2,1-c;1�,2�-e]phosphepine (5a) with different 

achiral phosphanes in a ratio of 1.05 to 1.05 equiv. in the 

presence of 1.0 equiv. of [Rh(cod) 2]BF 4. The results obtained 

for the hydrogenation of N-(1-phenylvinyl)acetamide 

(6a) under optimized reaction conditions are presented in 

Table 3. 

Table 3. Application of ligand mixtures in the asymmetric hydrogenation 

of N-(1-phenylvinyl)acetamide (6a). [a] 

Entry Ligand B Conversion [%] [b] ee [%] [b,c] 

1 5a �99 93 (R) 

2 PPh 3 �99 85 (R) 

3 P(p-MeO-C 6H 4) 3 �99 88 (R) 

4 P(p-Me-C 6H 4) 3 �99 81 (R) 

5 PCy 3 �99 74 (R) 



ligand 5a, 0.0025 mmol achiral ligand and 0.24 mmol substrate in 

2.0 mL toluene. [b] Conversion and ee values determined by GC 

[50 m Lipodex E (Macherey–Nagel), 80 °C, (R)-7a 26.7 min, (S)-7a 

28.3 min]. [c] The absolute configuration was determined by comparing 

the sign of specific rotation with reported data and the original 

sample (Aldrich). [5i] 

In general, we observed a slight decrease in enantioselectivity 

from that observed when using 2.1 equiv. of ligand 

5a. On the assumption that probably three different 

metal complexes could be formed, in particular, two homocombination 

products, the chiral [Rh(5a)(5a)(cod)]BF 4 and 

the achiral [Rh(L)(L)(cod)]BF 4, and the hetero-combination 

product [Rh(L)(5a)(cod)]BF 4, we deduce a significantly 

lower reaction rate or inactivity for the achiral complex 

[Rh(L)(L)(cod)]BF 4 relative to complex [Rh(5a)(5a)(cod)]- 

BF 4 or [Rh(L)(5a)(cod)]BF 4. Tricyclohexylphosphane 

(Table 3, Entry 5) was found to be the only exception, as 

we noticed a more pronounced decrease of the enantiomeric 

excess. 

Conclusions 

We demonstrated the application of monodentate 4,5-dihydro-3H-dinaphtho[2,1-c;1�,2�-e]phosphepines 

5 in the 

rhodium-catalyzed asymmetric hydrogenation of various 

enamides. The influences of different reaction parameters 

are presented. For the first time high enantioselectivity (up 

to 95% ee) for such reactions is obtained in the presence of 


FULL PAPER 

monodentate phosphanes. Best results were observed with 

aryl-substituted phosphepine ligands for reduction of N-(1phenylvinyl)acetamide, 

while alkyl-substituted phosphepine 

ligands yielded only low selectivity. 

Experimental Section 

All manipulations were performed under argon using standard 

Schlenk techniques. Diethyl ether and toluene were distilled from 

sodium benzophenone ketyl under argon. Methanol was distilled 

from Mg under argon. Dichloromethane was distilled from CaH2 under argon. The ligands 5 were synthesized according to our previously 

published protocols. [13] [Rh(cod) 2]BF4 (purchased from 

Fluka) was used without further purification. 

General Procedure for the Synthesis of Substituted N-(1-Phenylvinyl)acetamides 

6a–6e: To a stirred solution of methylmagnesium bromide 

(17.0 mmol, 3.0 mol/L diethyl ether, 6.0 mL) in diethyl ether 

(50 mL) at 0 °C a solution of the corresponding benzonitrile 

(17.0 mmol) in diethyl ether (20 mL) was added dropwise during a 

period of 30 minutes. After complete addition the solution was refluxed 

for eight hours. Within a few hours a yellow precipitate was 

formed. After refluxing the reaction mixture was cooled to 0 °C, 

and a solution of acetic anhydride (17.0 mmol) in diethyl ether 

(20 mL) was added carefully over 30 minutes. The reaction mixture 

was refluxed for eight hours. To the resulting suspension methanol 

was added at room temperature whilst stirring until all precipitates 

were dissolved (approximately 50 mL). The homogeneous solution 

was mixed with water/ethyl acetate (1:1, 100 mL). After phase separation 

the aqueous layer was extracted three times with ethyl acetate 

(50 mL). The combined organic layers were dried with MgSO4. After removing of the solvents the semi crystalline crude oil was 

purified by column chromatography (n-hexane/ethyl acetate, 1:1). 

Removal of the solvent yielded the crystalline products. [yields: (6a) 

1.51 g (55 %), (6b) 1.66 g (51 %), (6c) 1.50 g (46 %), (6d) 1.52 g 

(50%), (6e) 1.91 g (49 %)] 

General Procedure for the Synthesis of the Cyclic N-Acyl Enamide 

6f: A stirred solution of the corresponding ketone (30.3 mmol), hydroxylamine–hydrochloride 

(73 mmol) and pyridine (62.2 mmol) in 

ethanol (40 mL) was heated to 85 °C for a period of 16 hours. The 

solvent was removed, and the residue was dissolved in ethyl acetate/ 

water. The organic phase was washed two times with water (20 mL) 

and dried with MgSO4. After removal of the solvents the product 

was recrystallized from toluene. The corresponding ketoximine 

(18.6 mmol) was solved in toluene (30 mL) under argon. To the 

stirred solution acetic acid anhydride (55.9 mmol), acetic acid 

(55.9 mmol), and Fe powder (37.3 mmol, Aldrich 325 mesh) were 

added and then heated to 70 °C for 4 hours. The mixture was filtered 

through a plug of celite after cooling to room temperature. 

Dichloromethane was added to the filtrate, followed by washing 

with 2.0 m NaOH (2 ×25 mL) at 0 °C. The separated organic phase 

was concentrated to half volume. The crystalline product was obtained 

after 12 hours at 0 °C. The crystals were filtered and dried 

in vacuo. [overall yield: 2.05 g (59 %)] 

General Procedure for the Catalytic Hydrogenation of Enamides: A 

solution of enamide (0.24 mmol) and 1.0 mL solvent was transferred 

via syringe into the secured autoclave. Because of the poor 

solubility in toluene at room temperature the solution was heated 

to 50 °C before it was transferred. The catalyst was generated in 

situ by mixing [Rh(cod) 2]BF4 (0.0024 mmol) and the corresponding 

4,5-dihydro-3H-dinaphthophosphepine ligands (0.005 mmol) in 

1.0 mL solvent for a period of 10 min, and afterwards, it was trans- 

2916 

S. Enthaler, B. Hagemann, K. Junge, G. Erre, M. Beller 

ferred via syringe into the autoclave. Then, the autoclave was 

charged with hydrogen and the mixture was stirred at the required 

temperature. After the predetermined time the hydrogen was released 

and the reaction mixture passed through a short plug of 

silica gel. The enantioselectivity and conversion were measured by 

GC or HPLC without further modifications. 

Acknowledgments 

We thank M. Heyken, S. Buchholz and Dr. C. Fischer (all Leibniz- 

Institut für Katalyse e. V. an der Universität Rostock) for excellent 

technical assistance and Prof. Dr. S. Gladiali for general discussions. 

Generous financial support from the state of Mecklenburg-Western 

Pomerania and the BMBF is gratefully acknowledged. 

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Received: January 13, 2006 

Published Online: April 26, 2006 



5.2. Development of Practical Rhodium Phosphine Catalysts for the 

Hydrogenation of β–Dehydroamino Acid Derivates 

Stephan Enthaler, Giulia Erre, Kathrin Junge, Jens Holz, Armin Börner, Elisabetta Alberico, 

Ilenia Nieddu, Serafino Gladiali*, and Matthias Beller*, Org. Process Res. Dev. 2007, 11, 

568–577. 

Contributions 

Dr. Jens Holz carried out preliminary experiments with BINEPINE–ligands which are not 

stated in the article. Investigations with different metal precursors and defined complexes for 

instance catalysis with [Rh(6a)2(nbd)]SO3CF3 and [Rh(nbd)2]BF4 were realized by the group 

of Prof. Gladiali. Furthermore, ligands (R)–6a and 6e were synthesized by Dr. B. Hagemann.

Organic Process Research & Development 2007, 11, 568−577 

Development of Practical Rhodium Phosphine Catalysts for the Hydrogenation 

of �-Dehydroamino Acid Derivatives 

Stephan Enthaler, † Giulia Erre, † Kathrin Junge, † Jens Holz, † Armin Börner, †,‡ Elisabetta Alberico, § Ilenia Nieddu, | 

Serafino Gladiali,* ,| and Matthias Beller* ,† 

Leibniz Institut für Katalyse an der UniVersität Rostock e.V., Albert-Einstein Strasse 29a, 18059 Rostock, Germany, 

Institut für Chemie der UniVersität Rostock, Albert-Einstein Strasse 3a, 18059 Rostock, Germany, Istituto di Chimica 

Biomolecolare - CNR, traV. La Crucca 3, 07040 Sassari, Italy, and Dipartimento di Chimica, UniVersità di Sassari, 

Via Vienna 2, 07100 Sassari, Italy 

Abstract: 

The rhodium-catalyzed asymmetric hydrogenation of various 

�-dehydroamino acid derivatives to give optically active �-amino 

acids has been examined. Chiral monodentate 4,5-dihydro-3Hdinaphthophosphepines, 

which are easily tuned and accessible 

in a multi-10-g scale, have been used as ligands. The enantioselectivity 

is largely dependent on the nature of the substituent 

at the phosphorous atom and on the structure of the substrate. 

Applying optimized conditions up to 94% ee was achieved. 

Introduction 

The discovery of new effective drugs is an important 

challenge for industrial and academic research. During the 

last decades an intense area of research in medicinal 

chemistry was the development of peptide-based therapeutics, 

mainly constructed by R-amino acids. More recently, significant 

attention was also directed to non-natural �-amino 

acids, which are interesting building blocks for the synthesis 

of biologically active compounds such as �-lactam antibiotics, 

the taxol derivatives, and �-peptides (Scheme 1). 1 In 

view of the growing demand of chiral �-amino acids, an 

increasing number of synthetic methods have been established 

for their preparation such as homologation of R-amino 

acids, conjugate addition of amines to carbonyl compounds, 

Mannich reaction, hydrogenation etc. 1c,2 Within these methodologies, 

asymmetric catalytic hydrogenation constitutes the 

most attractive and versatile technology as to industrial 

applications due to the remarkable improvements achieved 

in the past few years in the asymmetric hydrogenation of 

�-dehydroamino acid derivatives. Good-to-excellent enan- 

* To whom correspondence should be addressed. E-mail: matthias.beller@ 

catalysis.de. Fax: 49 381 12815000. Telephone: 49 381 1281113. 

† Leibniz Institut für Katalyse e.V an der Universität Rostock. 

‡ Institut für Chemie der Universität Rostock. 

§ Istituto di Chimica Biomolecolare - CNR. 

| Dipartimento di Chimica, Università di Sassari. 

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such as MeDuPhos, catASium M, BINAP, BINAPO, 

BICP, TunaPhos, FerroTane, JosiPhos, DIOP, BPPM, P-Phos 

and others. 3 

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Chem. 2003, 68, 2490-2493. (n) Henschke, J. P.; Burk, M. J.; Malan, C. 

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2001, 66, 4148-4152. (q) Wu, H.-P.; Hoge, G. Org. Lett. 2004, 6, 3645- 

3647. (r) Hsiao, Y.; Rivera, N. R.; Rosner, T.; Krska, S. W.; Njolito, E.; 

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Zhang, S.; Sun, A.; Spannenberg, A.; Fischer, C.; Buschmann, H.; Heller, 

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568 • Vol. 11, No. 3, 2007 / Organic Process Research & Development 10.1021/op0602270 CCC: $37.00 © 2007 American Chemical Society 

Published on Web 12/30/2006

Scheme 1. Selection of biologically active compounds containing �-amino acid units 

(Scheme 3). 13 The first catalytic application of such a ligand 

(Ph-BINEPINE; 6a) in the Rh-catalyzed asymmetric hydroformylation 

of styrene was reported by one of us (S.G.) in 

the early 1990s. 11a In the following years, the Rostock group 

has expanded the structural diversity of the BINEPINE ligand 

family 6 into a library of ligands which has been screened 

with remarkable success (ee up to 95%) in the asymmetric 

(6) (a) Arnold, L. A.; Imobos, R.; Manoli, A.; de Vries, A. H. M.; Naasz, R.; 

Feringa, B. Tetrahedron 2000, 56, 2865-2878. (b) van den Berg, M.; 

Minnaard, A. J.; Schudde, E. P.; van Esch, J.; de Vries, A. H. M.; de Vries, 

J. G.; Feringa, B. L. J. Am. Chem. Soc. 2000, 122, 11539-11540. (c) 

Minnaard, A. J.; van den Berg, M.; Schudde, E. P.; van Esch, J.; de Vries, 

A. H. M.; de Vries, J. G.; Feringa, B. Chim. Oggi 2001, 19, 12-13. (d) 

Peña, D.; Minnaard, A. J.; de Vries, J. G.; Feringa, B. L. J. Am. Chem. 

Soc. 2002, 124, 14552-14553. (e) van den Berg, M.; Haak, R. M.; 

Minnaard, A. J.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L.; AdV. 

Synth. Catal. 2002, 344, 1003-1007. (f) van den Berg, M.; Minnaard, A. 

J.; Haak, R. M.; Leeman, M.; Schudde, E. P.; Meetsma, A.; Feringa, B. L.; 

de Vries, A. H. M.; Maljaars, C. E. P.; Willans, C. E.; Hyett, D.; Boogers, 

J. A. F.; Henderickx, H. J. W.; de Vries, J. G. AdV. Synth. Catal. 2003, 

345, 308-323. (g) Peña, D.; Minnaard, A. J.; de Vries, A. H. M.; de Vries, 

J. G.; Feringa, B. L.; Org. Lett. 2003, 5, 475-478. (h) Jiang, X.; van den 

Berg, M.; Minnaard, A. J.; Feringa, B.; de Vries, J. G. Tetrahedron: 

Asymmetry 2004, 15, 2223-2229. (i) Eelkema, R.; van Delden, R. A.; 

Feringa, B. L. Angew. Chem., Int. Ed. 2004, 43, 5013-5016. (j) Duursma, 

A.; Boiteau, J.-G.; Lefort, L.; Boogers, J. A. F.; de Vries, A. H. M.; de 

Vries, J. G.; Minnaard, A. J.; Feringa, B. L. J. Org. Chem. 2004, 69, 8045- 

8052. (k) Lefort, L.; Boogers, J. A. F.; de Vries, A. H. M.; de Vries, J. G. 

Org. Lett. 2004, 6, 1733-1735. (l) Bernsmann, H.; van den Berg, M.; Hoen, 

R.; Minnaard, A. J.; Mehler, G.; Reetz, M. T.; de Vries, J. G.; Feringa, B. 

L. J. Org. Chem. 2005, 70, 943-951. 

(7) (a) Reetz, M. T.; Sell, T. Tetrahedron Lett. 2000, 41, 6333-6336. (b) Reetz, 

M. T.; Mehler, G. Angew. Chem., Int. Ed. 2000, 39, 3889-3891. (c) Reetz, 

M. T.; Mehler, G.; Meiswinkel, G.; Sell, T. Tetrahedron Lett. 2002, 43, 

7941-7493. (d) Reetz, M. T.; Mehler, G.; Meiswinkel, G.; Sell, T. Angew. 

Chem., Int. Ed. 2003, 42, 790-793. (e) Reetz, M. T.; Mehler, G. Tetrahedron 

Lett. 2003, 44, 4593-4596. (f) Reetz, M. T.; Mehler, G.; Meiswinkel, A. 

Tetrahedron: Asymmetry 2004, 15, 2165-2167. (g) Reetz, M. T.; Li, X. 

G. Tetrahedron 2004, 60, 9709-9714. (h) Reetz, M. T.; Ma, J.-A.; Goddard, 

R. Angew. Chem., Int. Ed. 2005, 44, 412-414. (i) Reetz, M. T.; Fu, Y.; 

Meiswinkel, A. Angew. Chem. 2006, 118, 1440-1443. 

(8) (a) Claver, C.; Fernandez, E.; Gillon, A.; Heslop, K.; Hyett, D. J.; Martorell, 

A.; Orpen, A. G.; Pringle, P. G. Chem. Commun. 2000, 961-962. (b) 

Martorell, A.; Naasz, R.; Feringa, B. L.; Pringle, P. G. Tetrahedron: 

Asymmetry 2001, 12, 2497-2499. 

(9) (a) Hu, A.-G.; Fu, Y.; Xie, J.-H.; Zhou, H.; Wang, L.-X.; Zhou, Q.-L. Angew. 

Chem. 2002, 114, 2454-2456. (b) Fu, Y.; Guo, X.-X.; Zhu, S.-F.; Hu, A.- 

G.; Xie, J.-H.; Zhou, Q.-L. J. Org. Chem. 2004, 69, 4648-4655. (c) Fu, 

Y.; Hou, G.-H.; Xie, J.-H.; Xing, L.; Wang, L.-X.; Zhou, Q.-L. J. Org. 

Chem. 2004, 69, 8157-8160. 

(10) For other monodentate system see also: (a) Jerphagnon, T.; Renaud, L.-L.; 

Demonchauc, P.; Ferreira, A.; Bruneau, C. AdV. Synth. Catal. 2004, 346, 

33-36. (b) Bilenko, V.; Spannenberg, A.; Baumann, W.; Komarov, I.; 

Börner, A. Tetrahedron: Asymmetry 2006, 17, 2082-2087. 

hydrogenation with Rh- and Ru-catalysts of R-amino acid 

precursors, dimethyl itaconate, enamides and �-ketoesters. 13 

In the meantime, the utility of Ph-BINEPINE 6a has been 

demonstrated in a range of asymmetric reactions catalyzed 

by different transition metals such as the Pd-catalyzed 

umpoled-allylation of aldehydes and the Pt-catalyzed alkoxycyclization 

of 1,5-enynes. The ligand itself without any metal 

is an efficient chiral catalyst for the enantioselective acylation 

of diols, and for [3 + 2] cycloadditions and [4 + 2] 

annulations (Scheme 2). 11d,e,14 Quite recently excellent enantioselectivities 

have been scored in the Rh-catalyzed transfer 

hydrogenation of R-amino acid precursors and itaconic acid 

derivatives using formic acid as H-donor. Under these 

conditions �-dehydroamino acids derivatives have also been 

successfully hydrogenated, albeit in modest stereoselectivity. 11f 

Pursuing our ongoing research in hydrogenation chemistry, 

we report herein on the Rh-catalyzed asymmetric 

hydrogenation of �-dehydroamino acid derivatives. A multi- 

10-g scale synthesis of binaphthophosphepines is described, 

which allowed these ligands to be commercialized last year. 15 

(11) (a) Gladiali, S.; Dore, A.; Fabbri, D.; De Lucchi, O.; Manassero, M. 

Tetrahedron: Asymmmetry 1994, 5, 511-514. (b) Gladiali, S.; Dore, A.; 

Fabbri, D.; De Lucchi, O.; Valle, G. J. Org. Chem. 1994, 59, 6363-6371. 

(c) Gladiali, S.; Frabbi, D. Chem. Ber./ Rec. TraV. Chim. Pays Bas. 1997, 

130, 543-554. (d) Charruault, L.; Michelet, V.; Taras, R.; Gladiali, S.; 

Genêt, J.-P. Chem. Commun. 2004, 850-851. (e) Zanoni, G.; Gladiali, S.; 

Marchetti, A.; Piccinini, P.; Tredici, I.; Vidari, G. Angew. Chem., Int. Ed. 

2004, 43, 846-849. (f) Alberico, E.; Nieddu, I.; Taras, R.; Gladiali, S. HelV. 

Chim. Acta 2006, 89, 1716-1729. 

(12) (a) Chi, Y.; Zhang, X. Tetrahedron Lett. 2002, 43, 4849-4852. (b) Tang, 

W.; Wang, W.; Chi, Y.; Zhang, X. Angew. Chem., Int. Ed. 2003, 42, 3506- 

3509. (c) Chi, Y.; Zhou, Y.-G.; Zhang, X. J. Org. Chem. 2003, 68, 4120- 

4122. (d) Xiao, D.; Zhang, X. Angew. Chem., Int. Ed. 2001, 40, 3425- 

3428. (e) Xiao, D.; Zhang, Z.; Zhang, X. Org. Lett. 1999, 1, 1679-1681. 

(13) (a) Junge, K.; Oehme, G.; Monsees, A.; Riermeier, T.; Dingerdissen, U.; 

Beller, M. Tetrahedron Lett. 2002, 43, 4977-4980. (b) Junge, K.; Oehme, 

G.; Monsees, A.; Riermeier, T.; Dingerdissen, U.; Beller, M. J. Organomet. 

Chem. 2003, 675, 91-96. (c) Junge, K.; Hagemann, B.; Enthaler, S.; 

Spannenberg, A.; Michalik, M.; Oehme, G.; Monsees, A.; Riermeier, T.; 

Beller, M. Tetrahedron: Asymmetry 2004, 15, 2621-2631. (d) Junge, K.; 

Hagemann, B.; Enthaler, S.; Oehme, G.; Michalik, M.; Monsees, A.; 

Riermeier, T.; Dingerdissen, U.; Beller, M. Angew. Chem. 2004, 116, 5176- 

5179; Angew. Chem., Int. Ed. 2004, 43, 5066-5069. (e) Hagemann, B.; 

Junge, K.; Enthaler, S.; Michalik, M.; Riermeier, T.; Monsees, A.; Beller, 

M. AdV. Synth. Catal. 2005, 347, 1978-1986. (f) Enthaler, S.; Hagemann, 

B.; Junge, K.; Erre, G.; Beller, M. Eur. J. Org. Chem. 2006, 2912-2917. 

(14) (a) Wurz, R. P.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 12234-12235. (b) 

Vedejs, E.; Daugulis, O.; Diver, S. T. J. Org. Chem. 1996, 61, 430-431. 

(c) Wilson, J. E.; Fu, G. C. Angew. Chem., Int. Ed. 2006, 45, 1426-1429. 

Vol. 11, No. 3, 2007 / Organic Process Research & Development • 569

Scheme 2. Applications of ligand class 6 in asymmetric synthesis 

Results and Discussion 

The synthesis of binaphthophosphepines starts with diesterification 

of enantiomerically pure 2,2′-binaphthol 16 (98% 

ee) with trifluoromethanesulfonic acid anhydride in the 

presence of pyridine (Scheme 3). The corresponding diester 

was obtained in 99% yield, and subsequent nickel-catalyzed 

Kumada coupling with methyl magnesium bromide led to 

2,2′-dimethylbinaphthyl in 95% yield. 13,17 Two different 

synthetic strategies were established to obtain 4,5-dihydro- 

3H-dinaphtho[2,1-c;1′,2′-e]phosphepine ligands 6. On the one 

hand, double metalation of 2,2′-dimethylbinaphthyl with 

n-butyl lithium in the presence of TMEDA (N,N,N′,N′tetramethylethylenediamine) 

followed by quenching with 

commercially available dichlorophosphines gives ligands 6a 

(P-phenyl) and 6i (P-tert-butyl) in 60-83% yield. Both 

ligands have been synthesized on >10-g scale. In the second 

procedure the dilithiated dimethyl binaphthalene is quenched 

with diethylaminodichlorophosphine, giving the phosphepine 

5 which, upon treatment with gaseous HCl, is converted into 

4-chloro-4,5-dihydro-3H-dinaphtho[2,1-c;1′,2′-e]phosphepine 

in 80% yield. This enantiomerically pure chlorophosphine 

is easily coupled with various Grignard or lithium 

(15) The ligands Ph-BINEPINE (6a) and t-Bu-BINEPINE (6i) are commercially 

available by Degussa DHC (Degussa Homogeneous Catalysis, Rodenbacher 

Chaussee 4, building 097, 63457 Haunau (Wolfgang), Germany, (www.creavis.com/site_dhc/de/default.cfm)) 

with the product names catASium 

KPh (6a) and catASium KtB (6i). 

(16) Optically pure 2,2′-binaphthol is available on large scale from RCA (Reuter 

Chemische Apparatebau KG), Engesserstr. 4, 79108 Freiburg, Germany. 

(17) The synthesis of 2,2′-bistriflate-1,1′-binaphthyl (1.2 mol, 615 g, 92%) and 

2,2′-dimethyl-1,1′-binaphthyl (0.74 mol, 201 g, 96%) was carried out in 

large scale by the group of Zhang (See ref 11b). 

570 • Vol. 11, No. 3, 2007 / Organic Process Research & Development 

reagents to give a broad selection of ligand 6. The limited 

number of commercially available dichlorophosphines and 

the large diversity of Grignard compounds make the access 

through 4-chloro-4,5-dihydro-3H-dinaphtho[2,1-c;1′,2′-e]phosphepine 

the route of choice to a library of ligands 6. 

The syntheses of �-acetamido acrylates 7-11 and 14 were 

carried out according to literature protocols by reaction of 

the corresponding �-ketoester with NH4OAc followed by 

acylation of the �-amino acrylate intermediate. 3c,d E/Z- 

Isomers were separated by crystallization and column chromatography. 

Ethyl 3-acetamido-3-phenyl-2-propenoate (12) 

and methyl 3-benzamido butenoate (13) were synthesized 

by reaction of the corresponding �-amino acrylate with acyl 

chloride or benzoyl chloride. 3l 

To compare the behaviour of the Z- and E-isomers, initial 

catalytic runs were carried out separately on the (Z)- and 

(E)-methyl 3-acetamido butenoates (Z-7 and E-7, respectively) 

as substrates and 4-phenyl-4,5-dihydro-3H-dinaphtho- 

[2,1-c;1′,2′-e]phosphepine (6a) as our standard ligand. 13 

Typically, we used an in situ precatalytic mixture of 1 

mol % [Rh(cod)2]BF4 and 2.1 mol % of the corresponding 

ligand. All hydrogenation reactions were carried out in an 

8-fold parallel reactor array with a reactor volume of 3.0 

mL. 18 

We first focused our attention on the influence of the 

solvent and the hydrogen pressure. The first set of reactions 

was run at constant concentration in toluene, dichloromethane, 

methanol, ethanol, 19 and 2-propanol at three 

(18) Institute of Automation (IAT), Richard Wagner Str. 31/ H. 8, 18119 Rostock- 

Warnemünde, Germany.

Scheme 3. Synthetic approach to 4,5-dihydro-3H-dinaphtho[2,1-c;1′,2′-e]phosphepine ligands 6 

different pressures (2.5, 10.0, and 50.0 bar). Selected results 

are presented in Figure 1. 

In the case of hydrogenation of E-7 the best enantioselectivity 

was consistently achieved at the lowest pressure (2.5 

bar) and ranged between 42-79% ee, depending on the 

solvent. After 24 h the reaction was complete only in 

2-propanol, whereas lower conversions were observed in 

ethanol, methanol, and toluene. 20 No reaction at all took place 

in dichloromethane. The stereoselectivity decreased upon 

increasing the pressure of hydrogen to 10.0 bar or 50.0 bar. 

From these results 2-propanol and 2.5 bar were selected as 

solvent and pressure of choice, respectively, for the hydrogenation 

of the E-isomer (conversion: >99%; enantioselectivity: 

79%). The hydrogenation of Z-7 resulted in higher 

enantioselectivities in all the solvents (up to 92% ee). 

Notably, compared to E-7 the configuration of the prevailing 

enantiomer was always opposite. Furthermore, in ethanol and 

in methanol the enantioselectivity/pressure trend was reversed, 

the top value (92% ee) having been reached at the 

highest pressure (50.0 bar) compared to 86% ee at 2.5 bar. 

Full conversions were obtained in all the experiments, except 

in toluene (37%) and in dichloromethane (45%). These 

(19) The hydrogenation performed in ethanol and 2-propanol led exclusively to 

product 7. No transesterification was observed. 

(20) In the case of toluene we assume an inhibition of the catalyst by the solvent, 

due to the formation of catalytical inactive rhodium-arene complexes. 

Heller, D.; Drexler, H.-J.; Spannenberg, A.; Heller, B.; You, J.; Baumann, 

W. Angew. Chem., Int. Ed. 2002, 41, 777-780. 

results indicated ethanol and methanol as the best solvents 

and 50.0 bar as the pressure of choice for the hydrogenation 

of the Z-isomer (conversion: >99%; enantioselectivity: 

92%). 

No incorporation of deuterium in the product was noticed 

upon running the reaction in methanol-d4. This is in line with 

the absence in the reduction process of any interference of 

transfer hydrogenation as well as of protonolysis of the 

Rh-C bond of an alkyl rhodium intermediate. 21 Two facets 

deserving mention are (1) the Z-isomer gives higher ee’s than 

the E-isomer, whereas in most cases the opposite behaviour 

has been reported 3 and (2) the configuration switches 

depending on the different geometry of the double bond, 

which has been scarcely reported. 3c,22 

Next, we investigated the influence of temperature on 

enantioselectivity and conversion as shown in Figure 2. 23 

Applying our model ligand 6a we found a pronounced 

negative effect on the enantioselectivity at higher temperatures 

for both isomers. Interestingly, the loss of enantioselectivity 

for the hydrogenation of E-7 is higher than for Z-7 

(10 °C: E-7 79% ee (R) and Z-7 88% ee (S); 90 °C: E-7 

rac and Z-7 60% ee (S)). 

(21) Tsukamoto, M.; Yoshimura, M.; Tsuda, K.; Kitamura, M. Tetrahedron 2006, 

62, 5448-5453. 

(22) Hu, X.-P.; Zheng, Z. Org. Lett. 2005, 7, 419-422. 

(23) Jerphagnon, T.; Renaud, J.-L.; Demonchaux, P.; Ferreira, A.; Bruneau, C. 

Tetrahedron: Asymmetry 2003, 14, 1973-1977. 


Figure 1. Solvent and pressure variation. Reactions were 

carried out at 10 °C for 24 h with 0.0024 mmol [Rh(cod)2]BF4, 

0.005 mmol ligand 6a and 0.24 mmol substrate in 2.0 mL of 

solvent. Conversions and ee’s were determined by GC (50 m 

Chiraldex �-PM, 130 °C, (S)-7a 15.1 min, (R)-7a 16.4 min). The 

absolute configuration was determined by comparison with 

reported data. 3l 

For estimating the feasible enantioselectivity at lower 

temperature we analysed the corresponding Eyring plot 24 for 

both isomers. As a consequence we considered 10 °C as 

temperature of choice, because of good enantioselectivity 

and also acceptable reaction times. 

The original protocol used for the synthesis of methyl 

3-acetamido butenoate (7) gives a mixture of E- and 

Z-isomers whose composition depends on the reaction 

conditions. 1f Although separation of the isomers by fractional 

(24) Buschmann, H.; Scharf, H.-D.; Hoffmann, N.; Esser, P. Angew. Chem. 1991, 

103, 480-518. 


Figure 2. Dependency of enantioselectivity versus temperature. 

Reactions were carried out at corresponding temperature for 

1-24 h with 0.0024 mmol [Rh(cod)2]BF4, 0.005 mmol ligand 

6a and 0.24 mmol substrate in 2.0 mL of 2-propanol. Conversions 

and ee’s were determined by GC (50 m Chiraldex �-PM, 

130 °C, (S)-7a 15.1 min, (R)-7a 16.4 min). 

Figure 3. Dependency of enantioselectivity versus E/Z ratio. 

Reactions were carried out at 10 °C for 24 h with 0.0024 mmol 

[Rh(cod)2]BF4, 0.005 mmol ligand 6a and 0.24 mmol substrate 

in 2.0 mL of ethanol. Conversions and ee’s were determined 

by GC (50 m Chiraldex �-PM, 130 °C, (S)-7a 15.1 min, (R)-7a 

16.4 min). 

crystallization is feasible, the selective hydrogenation of the 

mixture is clearly advantageous. This prompted us to explore 

the hydrogenation of different E/Z ratios including the 

mixture obtained from the synthesis (Figure 3). The results 

showed a linear decrease of enantioselectivity for all mixtures 

and demostrated that the hydrogenation of the single isomers 

led to highest enantioselectivity. 

Recently, Heller and Börner have reported kinetics and 

mechanistic investigations for the hydrogenation of E-7 and 

Z-7 through the use of bidentate phosphine ligands. The 

mentioned results modified the existent declaration that the

Figure 4. Dependency of hydrogen consumption versus reaction 

time. Reactions were carried out under isobaric conditions 

(1.0 bar) at 25 °C. [Rh(cod)2]BF4 (0.0072 mmol) and 0.015 mmol 

ligand 6a were stirred for 10 min under hydrogen atmosphere 

in 10.0 mL of methanol. Afterwards the substrate (0.72 mmol) 

was added in 1.0 mL of methanol. The conversions and ee’s 

were determined by GC (50 m Chiraldex �-PM, 130 °C, (S)-7a 

15.1 min, (R)-7a 16.4 min). 

reaction rate for hydrogenation of E-isomers is higher than 

that for the Z-isomers, because in some cases the opposite 

behaviour was observed. 3g 

To classify ligand 6a we recorded the hydrogen uptake 

in relation to the reaction time for the asymmetric hydrogenation 

of E-7 and Z-7 with our catalyst in isobaric conditions 

and under normal pressure of hydrogen (Figure 4). 

To minimize the interfering effect of cyclooctadiene (cod), 

the precatalyst was stirred for 10 min under hydrogen 

atmosphere before adding the substrate E-7 or Z-7. We were 

surprised to see that, unlike the case of most bidentate 

ligands, in our case at 50% conversion it was the Z-isomer 

which was hydrogenated faster (about 3.5 times the Eisomer). 

For gaining an insight into the structure of the catalyst, 

the hydrogenation of Z-7 was perfomed using the preformed 

complex [Rh(6a)2(nbd)] + CF3SO3 - as the catalyst. This 

cationic complex was prepared as previously reported by 

us, 11f and the reaction was run in MeOH at 5 bar at 25 °C. 

Under these conditions, Z-7 was completely hydrogenated 

in 12 h to give the (S)-enantiomer in 92% ee. This result is 

quite close to the one obtained with the catalysts prepared 

in situ by adding 2 equiv of the ligand 6a either to 

[Rh(nbd)2] + BF4 - (89% ee) or to [Rh(cod)2] + BF4 - (88% ee). 

From this it follows that the catalytically active species most 

likely contain two monodentate P-ligands per Rh center and 

that the ancillary diolefin ligand has a negligible effect, if 

any, on the stereoselectivity, while the anion may exert some 

influence. Further support to the presence of two ligands 

around the metal comes from the search of nonlinear effect 

(NLE) in the model reaction. 25 A set of hydrogenations was 

performed on both the isomers using various samples of 

Figure 5. Dependency of the optical purity of ligand 6a on 

product selectivity. Reactions were carried out at 10 °C for 24 h 

with 0.0024 mmol [Rh(cod)2]BF4, 0.005 mmol ligand 6a and 

0.24 mmol substrate in 2.0 mL of methanol. Conversions and 

ee’s were determined by GC (50 m Chiraldex �-PM, 130 °C, 

(S)-7a 15.1 min, (R)-7a 16.4 min). 

ligand 6a of different enantiomeric purity, and the ee’s 

observed have been plotted against the enantiomeric purity 

of the ligand (Figure 5). For both Z-7 and E-7 a positive 

nonlinear effect, which implies the bonding of at least two 

ligands to the rhodium, is clearly apparent. Similar results 

were reported by Reetz, 7i Zhou, 9b and Feringa 6f for the 

asymmetric hydrogenation of itaconic esters or R-amino acid 

derivatives by the use of different monodentate P-donor 

ligands. To verify the positive nonlinear effect we decreased 

the amount of ligand to 1 equiv with respect to rhodium. 

Here, we observed a diminished reaction rate compared to 

the rate of hydrogenation with 2 equiv of ligand. In addition, 

the amount of ligand was increased to 4 equiv with respect 

to rhodium, but also in this case a reduced reaction rate was 

monitored. 

In previous studies we have shown the pronounced effect 

that the substitution pattern at the P-centre of BINEPINE 

ligands has on the stereoselectivity of the asymmetric 

process. 13 In order to evaluate this substituent effect the 

asymmetric hydrogenation of E-7 and Z-7 was performed 

in the optimized conditions previously devised with nine 

different 4,5-dihydro-3H-dinaphtho[2,1-c;1′,2′-e]phosphepines 

(6a-6i) (E-7: 2.5 bar hydrogen pressure, 2-propanol, 

10 °C, 24 h; Z-7: 50.0 bar, ethanol, 10 °C, 24 h) (Table 1). 

In the hydrogenation of E-7 the best enantioselectivities 

up to 90, 88, and 87% ee, respectively, were achieved with 

ligands 6g, 6d, and much to our surprise, with 6i (Table 1, 

entries 7, 4, and 9). The last one has always given quite poor 

results in the other benchmark tests where it has been 

screened. The presence of electron-donating groups on the 

P-aryl substituent has a positive effect on the stereoselectivity 

(Table 1, entries 4, 6, and 7), whereas the opposite occurs 

for electron-withdrawing groups (Table 1, entry 2). This trend 

(25) (a) Girard, C.; Kagan, H. B.; Angew. Chem. 1998, 110, 3088-3127. (b) 

Faller, J. W.; Parr, J. J. Am. Chem. Soc. 1993, 115, 804-805. 


Table 1. Hydrogenation of E-7 and Z-7 with different 

4,5-dihydro-3H-dinaphtho[2,1-c;1′,2′-e]phosphepines (6a-6i) 

entry ligand isomer a conv. [%] b ee [%] b isomer c conv. [%] b ee [%] b 

1 6a E >99 79 (R) Z >99 92 (S) 

2 6b E 91 40 (R) Z >99 32 (S) 

3 6c E 80 69 (R) Z >99 80 (S) 

4 6d E >99 88 (R) Z >99 86 (S) 

5 6e E >99 20 (R) Z >99 rac 

6 6f E 91 81 (R) Z 90 40 (S) 

7 6g E >99 90 (R) Z >99 89 (S) 

8 6h E >99 76 (R) Z 5 38(S) 

9 6i E >99 87 (R) Z 3 60(S) 

a All reactions were carried out at 10 °C under 2.5 bar pressure of hydrogen 

for 24 h with 0.0024 mmol [Rh(cod)2]BF4, 0.005 mmol ligand and 0.24 mmol 

substrate in 2-propanol (2.0 mL). b Conversions and ee’s were determined by 

GC (50 m Chiraldex �-PM, 130 °C, (S)-7a 15.1 min, (R)-7a 16.4 min). The 

absolute configuration was determined by comparing with reported data. 3l c All 

reactions were carried out at 10 °C under 50.0 bar pressure of hydrogen for 24 

h with 0.0024 mmol [Rh(cod)2]BF4, 0.005 mmol ligand and 0.24 mmol substrate 

in ethanol (2.0 mL). 

is similar to the one observed in the hydrogenation of Z-7 

although in that case the best ee was scored with the plain 

phenyl ligand 6a. Alkyl-substituted phosphepines 6h and 6i 

produced catalysts of negligible activity in hydrogenation 

of this substrate (Table 1, entries 8 and 9). 

To explore scope and limitation of our ligand toolbox, 

the asymmetric hydrogenation of a range of �-dehydroamino 

acids derivatives was performed under optimized conditions 

(Table 2). First the influence of the ester-group on the 

hydrogenation of both Z- and E-isomers was investigated in 

detail. For E-7 changing from methyl to isopropyl ester 

resulted consistently in a slight decrease of stereoselectivity, 

whereas in the case of the Z-isomer no reliable correlation 

between ester functionality and enantioselectivity was detected. 

Notably, a diminished yield for all hydrogenations 

of Z-9 was attained (Table 2). 

Finally, the influence of � 3 - and � 2 -substitution was 

investigated on a set of seven different substrates (Scheme 

4 and Table 3). While substitution of a methyl with an ethyl 

group has negligible effects, an increase in the branching of 

the alkyl group resulted in an improved selectivity with 

ligands 6g and 6i. Furthermore, we also carried out a 

substitution in the � 3 -position by an aromatic group (compound 

Z-12). As a tendency, depletion of conversion and 

enantioselectivity was observed in comparison to Z-8 (Table 

1, entries 1-7 and Table 2, entries 15-21). A similar 

negative effect was found after substitution of the acyl 

protecting group by benzoyl and subjecting Z-13 in the 

hydrogenation reaction (Table 3, entries 15-21). 


Table 2. Influence of ester group on conversion and 

enantioselectivity 


1 6a E-8 98 83 (R) Z-8 >99 94 (S) 

2 6b E-8 79 46 (R) Z-8 >99 rac 

3 6c E-8 65 20 (R) Z-8 >99 36 (S) 

4 6d E-8 98 84 (R) Z-8 >99 83 (S) 

5 6g E-8 97 84 (R) Z-8 >99 85 (S) 

6 6h E-8 >99 66 (R) Z-8 >99 rac 

7 6i E-8 >99 80 (R) Z-8 >99 rac 

8 6a E-9 >99 70 (R) Z-9 52 78 (S) 

9 6b E-9 63 40 (R) Z-9 23 46 (S) 

10 6c E-9 73 20 (R) Z-9 61 24 (S) 

11 6d E-9 >99 76 (R) Z-9 69 91 (S) 

12 6g E-9 92 72 (R) Z-9 55 73 (S) 

13 6h E-9 >99 66 (R) Z-9 34 rac 

14 6i E-9 >99 76 (R) Z-9 32 6 (S) 



substrate in 2-propanol (2.0 mL). b Conversions and ee’s were determined by 

GC (8 (25 m Lipodex E, 70/40-8-180, (R)-8a 33.2 min, (S)-8a 33.4 min), 9 (25 

m Lipodex E, 70/25-10-180, (R)-9a 33.2 min, (S)-9a 33.4 min). The absolute 

configurations were determined by comparing the sign of specific rotation with 

reported data. 3d c All reactions were carried out at 10 °C under 50.0 bar pressure 

of hydrogen for 24 h with 0.0024 mmol [Rh(cod)2]BF4, 0.005 mmol ligand and 

0.24 mmol substrate in ethanol (2.0 mL). 

Scheme 4. Asymmetric hydrogenation of methyl 

2-acetamidocylopent-1-enecarboxylate (14) a 



substrate in ethanol (2.0 mL). Conversion, de’s and ee’s were determined by 

GC (25 m Chirasil Val, 120 °C, 14a1 26.8 min, 14a2 27.6 min, 14a3 52.1 min, 

14a4 53.0 min). 

As an example for tetra-substituted �-dehydroamino acid 

precursor (� 3 - and � 2 -substitution) we tested methyl2acetamidocyclopent-1-enecarboxylate 

(14) 26 under optimized 

conditions for Z-isomers (Scheme 4). In the majority of cases 

excellent diastereoselectivities up to >99% de were achieved, 

accompanied by good to moderate conversions. Best enantioselectivities 

up to 76% ee were obtained by utilizing 

ligands 6a and 6b (Scheme 4). 

An additional possibility offered by monodentate ligands 

from which one can profit in asymmetric catalysis is the 

possibility to introduce in the coordination sphere of the 

(26) Tang, W.; Wu, S.; Zhang, X. J. Am. Chem. Soc. 2003, 125, 9570-9571.

Table 3. Influence of � 3 -substitution on conversion and 

enantioselectivity 


1 6a E-10 >99 78 (R) Z-10 98 86 (S) 

2 6b E-10 91 44 (R) Z-10 96 58 (S) 

3 6c E-10 95 60 (R) Z-10 >99 20 (S) 

4 6d E-10 >99 78 (R) Z-10 97 50 (S) 

5 6g E-10 >99 75 (R) Z-10 93 48 (S) 

6 6h E-10 >99 72 (R) Z-10 97 rac 

7 6i E-10 >99 84 (R) Z-10 47 24 (R) 

8 6a E-11 >99 26 (R) Z-11 >99 78 (S) 

9 6b E-11 39 42 (R) Z-11 99 68 (S) 

10 6c E-11 88 70 (R) Z-11 99 28 (S) 

11 6d E-11 50 60 (R) Z-11 94 26 (S) 

12 6g E-11 >99 88 (R) Z-11 94 68 (S) 

13 6h E-11 98 34 (R) Z-11 67 rac 

14 6i E-11 >99 90 (R) Z-11 10 58 (R) 

15 6a Z-12 99 70 (R) Z-13 19 70 (-) 

16 6b Z-12 46 26 (R) Z-13 9 4 (-) 

17 6c Z-12 90 47 (R) Z-13 7 46(+) 

18 6d Z-12 95 52 (R) Z-13 99 76 (S) 

3 6a PCy3 Z a >99 78 (S) 

4 6i 6i E b >99 87 (R) 

5 6i PPh3 E b >99 34 (R) 

6 6i PCy3 E b >99 88 (R) 

7 6i 15 d E b 21 12 (R) 



substrate in ethanol (2.0 mL). b All reactions were carried out at 10 °C under 

2.5 bar pressure of hydrogen for 24 h with 0.0024 mmol [Rh(cod)2]BF4, 0.005 

mmol ligand and 0.24 mmol substrate in 2-propanol (2.0 mL). c Conversions 

and ee’s were determined by GC (50 m Chiraldex �-PM, 130 °C, (S)-7a 15.1 

min, (R)-7a 16.4 min). The absolute configuration was determined by comparing 

with reported data. 3l d 15 ) tris(2,4-di-tert-butylphenyl)phosphite. 

of 1.05 to 1.05 equiv of the two ligands with respect to 1.0 

equiv of [Rh(cod)2]BF4, and the reactions were carried out 

under the optimized conditions defined above. As a general 

trend, the heterocombination of monodentate ligands was 

always less stereoselective compared to the homocombination 

of the pivotal ligands (Table 4). There was just one 

notable exception for the system 6i/tricyclohexylphosphine 

(Table 4, entry 6) which gave the same ee as obtained when 

6i was used alone. Even if these results do not permit to 

draw any substantial conclusion, we may infer that in these 

conditions the catalytic activity of the different complexes 

which are formed in solution lies in the same range and that 

they compete for the substrate. 

Summary 

In conclusion, we have shown that monodentate chiral 

4,5-dihydro-3H-dinaphtho[2,1-c;1′,2′-e]phosphepine ligands 

can be synthesized on multi-10-g scale from 2,2′-binaphthol. 

They can be tuned easily by variation of the substituent at 

the P-atom. This class of ligands can be used for various 

rhodium- and ruthenium-catalyzed hydrogenations. For the 

first time their application towards the synthesis of �-amino 

acid derivatives is shown, and enantioselectivities up to 94% 

ee were achieved. 


All manipulations were performed under argon 

atmosphere using standard Schlenk techniques. Toluene, 

n-hexane, and diethyl ether were distilled from sodium 

benzophenone ketyl under argon. Methanol was distilled 

from magnesium under argon. Ethanol and 2-propanol were 


distilled from sodium under argon. Methylene chloride was 

distilled from CaH2 under argon. Ligands 6 were synthesized 

according to our previously published protocols. 13 [Rh(cod)2]- 

BF4 (purchased from Fluka) was used without further 

purification. The synthesis of (S)-2,2′-dimethyl-1,1′-binaphthyl 

in a 200-g scale has been described in the literature. 12b 

Synthesis of 4-Phenyl-4,5-dihydro-3H-dinaphtho[2,1c;1′,2′-e]phosphepine 

(6a) and 4-tert-Butyl-4,5-dihydro- 

3H-dinaphtho[2,1-c;1′,2′-e]phosphepine (6i) on 10-g Scale. 

Synthesis of the Dilithio Species. A solution of n-BuLi (0.19 

mol, 120 mL, 1.6 M in n-hexane) was concentrated under 

vacuum and the residual oil dissolved in diethyl ether (60 

mL). After cooling the mixture to 0 °C a solution of (S)- 

2,2′-dimethyl-1,1′-binaphthyl (74.5 mmol, 21 g) in diethyl 

ether (140 mL) was added over a dropping funnel during 20 

min to give a red solution. Afterwards TMEDA (192 mmol, 

28.6 mL, distilled over CaH2) was added slowly, and the 

resulting solution was kept for 24 h at room temperature, 

yielding deep red crystals. The supernatant solution was 

decanted via a tube. The crystals were washed two times 

with dry n-hexane (30 mL, removed by a tube) and dried 

under vacuum to give 60-80% yield (24.6-37.8 g). 

Synthesis of the 4-Phenyl-4,5-dihydro-3H-dinaphtho[2,1c;1′,2′-e]phosphepine 

(6a). Starting with the dilithium salt of 

(S)-2,2′-dimethyl-1,1′-binaphthyl (24.5 g, 44.4 mmol) in n-hexane 

(130 mL) a solution of phenyl dichlorophosphine (6.8 mL, 

50.3 mmol) in n-hexane (55 mL) was added at 0 °C. After 

2 h refluxing, the reaction mixture was quenched with water/ 

toluene. The organic layer was separated and dried over 

MgSO4. The ligand 6a was purified by column chromatography 

in dry toluene and gave light-yellow foam (12.9 g; 75%). 

Synthesis of the 4-tert-Butyl-4,5-dihydro-3H-dinaphtho- 

[2,1-c;1′,2′-e]phosphepine (6i). Starting with the dilithium 

salt of (S)-2,2′-dimethyl-1,1′-binaphthyl (24.5 g, 44.4 mmol) 

in n-hexane (130 mL) a solution of tert-butyl dichlorophosphine 

(8 g, 50.3 mmol) in n-hexane (55 mL) was added at 

0 °C. After 3 h refluxing, the reaction mixture was quenched 

with water/toluene. The organic layer was separated and dried 

over MgSO4. The ligand 6i was purified by crystallization 

from toluene (13.2 g; 81%). 

General Synthesis of �-Dehydroamino Acid Derivatives 

7-11 and 14. 3c To a solution of NH4OAc (0.36 mol) 

in methanol, ethanol, or 2-propanol (depending on the esterfunctionality 

(100 mL)) was added the corresponding �-ketoester 

(0.07 mol). After stirring for 60 h at room temperature 

the solvent was removed, and a mixture of CHCl3 and water 

was added. The organic layer was washed with water (3 × 

50 mL) and brine (50 mL) and dried over Na2SO4. The 

solvent was evaporated under reduced pressure, yielding the 

corresponding 3-amino-2-alkenoate. The 3-amino-2-alkenoate 

(0.07 mol), pyridine (0.13 mol), and acetic anhydride 

(0.32 mol) were dissolved in THF (50 mL) and stirred for 

12hat70°C (procedure A) or 95 °C (procedure B). The 

solution was reduced to half of the volume and ethylacetate 

was added. After washing with water, HCl, NaHCO3, brine 

and drying over Na2SO4, the solvent was removed. 

Procedure A (E-Isomer Enriched Residue). Dissolving the 

residue in ethylacetate/n-hexane (1:1) and storing the solution 


overnight at -20 °C yielded the E-isomers of �-dehydroamino 

acid derivatives 7-11, which were recrystallized 

three times from ethylacetate/n-hexane (1:1) to give colorless 

crystals [yield of the main fraction referred to �-ketoester: 

E-7: 1.4 g (11%), E-8: 1.2 g (10%), E-9: 1.5 g (11%), 

E-10: 1.4 g (12%), E-11: 1.8 g (14%)]. 

Procedure B (Z-isomer Enriched Residue). The pure 

Z-isomer was obtained by column chromatography (eluent: 

ethylacetate/n-hexane, 1:1 or 1:2) [yield referred to �-ketoester: 

Z-7: 4.3 g (39%), Z-8: 1.2 g (35%) (0.035 mmol 

�-ketoester), Z-9: 6.0 g (46%), Z-10: 1.6 g (26%) (0.035 

mmol �-ketoester), Z-11: 4.0 g (31%)]. In the case of methyl 

2-acetamidocyclopent-1-enecarboxylate (14) purification was 

carried out by crystallization (3×) from ethylacetate/n-hexane 

(1:1), yielding brown crystals [yield of the main fraction: 

4.1 g (32%)]. 

Synthesis of Ethyl 3-Acetamido-3-phenyl-2-propenoate 

(Z-12). 3l To a solution of NH4OAc (0.65 mol) in ethanol 

(100 mL) was added the corresponding �-ketoester (0.13 

mol). After stirring for 60 h at room temperature the solvent 

was removed, and a mixture of CHCl3 and water was added. 

The organic layer was washed with water (3 × 50 mL) and 

brine (50 mL) and dried over Na2SO4. The solvent was 

evaporated under reduced pressure, yielding the corresponding 

3-amino-2-alkenoate. To a stirred solution of the corresponding 

3-amino-2-alkenoate (0.026 mmol) and pyridine 

(0.046 mol) in toluene (50 mL) was added dropwise a 

solution of acetyl chloride (0.027 mol) in toluene (10 mL) 

at 0 °C. The mixture was stirred for 48 h at 25 °C. A further 

amount of acetylchloride (0.027 mol) in toluene (10 mL) 

was added at 0 °C, and the resulting mixture was stirred for 

48 h. After quenching with aqueous NH4H2PO4 solution the 

mixture was extracted with ethylacetate (3 × 50 mL). The 

organic layer was washed with water (2 × 50 mL) and dried 

over Na2SO4. The solvents were removed in vacuo, and the 

obtained yellow oil was purified by column chromatography 

(eluent: ethylacetate/n-hexane, 1:1), yielding yellow crystals 

[yield: Z-12: 0.59 g (10%)]. 

Synthesis of Methyl 3-Benzamido-2-butenoate (Z-13). 3l 

To a solution of NH4OAc (0.65 mol) in ethanol (100 mL) 

was added the corresponding �-ketoester (0.13 mol). After 

stirring for 60 h at room temperature the solvent was 

removed, and a mixture of CHCl3 and water was added. The 

organic layer was washed with water (3 × 50 mL) and brine 

(50 mL) and was dried over Na2SO4. The solvent was 

evaporated under reduced pressure, yielding the corresponding 

3-amino-2-alkenoate. To a stirred solution of the corresponding 

3-amino-2-alkenoate (0.026 mmol) and pyridine 

(0.046 mol) in diethylether (70 mL) was added dropwise a 

solution of benzoyl chloride (0.027 mol) in toluene (10 mL) 

at -30 °C. The mixture was stirred for 12 h at -30 °C and 

for 24 h at room temperature. After quenching with aqueous 

water the mixture was extracted with ethylacetate (3 × 50 

mL). The organic layer was washed with HCl (1 mol/L) and 

brine and dried over Na2SO4. The solvents were removed in 

vacuo, and the obtained yellow oil was purified by column 

chromatography (eluent: ethylacetate/n-hexane, 1:1), yielding 

crystals [yield: Z-13: 2.9 g (9%)].

General Procedure for the Catalytic Hydrogenation 

of �-Dehydroamino Acid Derivatives. A solution of the 

�-dehydroamino acid derivative (0.24 mmol) and 1.0 mL of 

solvent was transferred via syringe into an autoclave charged 

with argon. The catalyst was generated in situ by stirring 

[Rh(cod)2]BF4 (0.0024 mmol) and the corresponding 4,5dihydro-3H-dinaphthophosphepine 

ligand (0.005 mmol) in 

1.0 mL of solvent for a period of 10 min and afterwards 

transferring via syringe into the autoclave. The autoclave was 

then charged with hydrogen and stirred at the required 

temperature. After the predetermined time the hydrogen was 

released, and the reaction mixture passed through a short 

plug of silica gel. The conversion was measured by GC or 

1 H NMR and the enantioselectivity by GC or HPLC. 

Acknowledgment 

We thank Mrs. M. Heyken, Mrs. C. Voss, Mrs. G. 

Wenzel, Mrs. K. Schröder, Mrs. S. Buchholz, and Dr. C. 

Fischer (all Leibniz Institut für Katalyse e.V. an der 

Universität Rostock) for excellent technical and analytical 

assistance. Dr. B. Hagemann is gratefully thanked for the 

syntheses of ligands 6e and (R)-6a. Generous financial 

support from the state of Mecklenburg-Western Pomerania 

and the BMBF as well as the Deutsche Forschungsgemeinschaft 

(Leibniz-Price) is gratefully acknowledged. 

Received for review October 30, 2006. 

OP0602270 



5.3. Enantioselective rhodium–catalyzed hydrogenation of enol 

carbamates in the presence of monodentate phosphines 

Stephan Enthaler, Giulia Erre, Kathrin Junge, Dirk Michalik, Anke Spannenberg, 

Serafino Gladiali, and Matthias Beller*, Tetrahedron: Asymmetry, 2007, 18, 1288– 

1298. 

Contributions 

The synthetic route to ligand 7 was carried by G. Erre via compound 5a and 6. Suitable x–ray 

crystals of compound 5b were grown by Dr. K. Junge, while crystals for oxide 6 were 

obtained by G. Erre. The synthesis of substrates 9, 10, 11, 14 and the corresponding 

hydrogenation experiments stated in table 2 and table 3 were performed by G. Erre.

Enantioselective rhodium-catalyzed hydrogenation of enol carbamates 

in the presence of monodentate phosphines 

Stephan Enthaler, a Giulia Erre, a Kathrin Junge, a Dirk Michalik, a Anke Spannenberg, a 

Fabrizio Marras, b Serafino Gladiali b and Matthias Beller a, * 

a Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany 

b Dipartimento di Chimica, Università di Sassari, Via Vienna 2, 07100 Sassari, Italy 

Received 27 March 2007; accepted 1 June 2007 

Abstract—The rhodium-catalyzed asymmetric hydrogenation of different acyclic and cyclic enol carbamates to give optically active carbamates 

has been examined in the presence of chiral monodentate ligands based on a 4,5-dihydro-3H-dinaphthophosphepine motif 4. 

The enantioselectivity is largely dependent upon the reaction conditions, the nature of substituents on the phosphorus ligand and structure 

of the enol carbamate. By applying the optimized reaction conditions, enantioselectivities of up to 96% ee have been achieved. 

Ó 2007 Elsevier Ltd. All rights reserved. 


The importance of enantiomerically pure compounds is 

demonstrated by their widespread application as either 

building blocks or intermediates for the synthesis of pharmaceuticals, 

agrochemicals, polymers, natural compounds, 

auxiliaries, ligands and synthons in organic syntheses. 1 To 

serve the growing demand for enantiomerically pure compounds, 

various synthetic approaches have been developed. 

Within the different molecular transformations to chiral 

compounds, catalytic reactions offer an efficient and 

versatile strategy and present a key technology for the 

advancement of ‘green chemistry’, specifically for waste 

prevention, reducing energy consumption, achieving high 

atom efficiency and generating advantageous economics. 2 

In this regard, the use of molecular hydrogen in reductions 

of C@C, C@O andC@N bonds is one of the most extensively 

studied fields. For activation of the hydrogen and 

transfer of chirality, the use of transition metal catalysts 

containing chiral ligands are essential. Over a period of 

nearly 30 years, the synthesis of new ligands focused mainly 

on bidentate phosphorus systems, because of the promising 

results in the first few years of homogeneous asymmetric 

hydrogenation. However, at the end of the 20th century, 

the situation changed and monodentate ligands received 

* Corresponding author. Tel.: +49 381 1281 113; fax: +49 381 1281 

5000; e-mail: Matthias.Beller@catalysis.de 

0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. 

doi:10.1016/j.tetasy.2007.06.001 

Tetrahedron: Asymmetry 18 (2007) 1288–1298 

more attention. 3,4 The advantages of monodentate phosphorus 

ligands compared to bidentate ligands are their easier 

synthesis, high tunability and even a higher efficiency in 

the transfer of chiral information as observed in several 

cases. Important contributions in this field with excellent 

enantioselectivities for various classes of substrates were reported 

by Feringa and de Vries et al. 5 (phosphoramidites), 

Reetz et al. 6 (phosphites), Pringle and Claver et al. 7 (phosphonites) 

and Zhou et al. (spiro phosphoramidites). 8 

Following the effort of one of us (S.G.) 9 and parallel to the 

work of Zhang, 10 we constructed a ligand library of 

approximately 25 different monodentate phosphines based 

on a 4,5-dihydro-3H-dinaphtho[2,1-c;1 0 ,2 0 -e]phosphepine 

framework 4 (Scheme 1), which is reminiscent of the 1,1 0 - 

binaphthol core, which is present in the ligands mentioned 

above (Scheme 1). 11 The potential of this ligand class 4 in 

asymmetric hydrogenation with molecular hydrogen, such 

as the reduction of a-amino acid precursors, dimethyl 

itaconate, enamides and b-ketoesters achieving enantioselectivities 

up to 95% ee was previously reported by us. 11 

Moreover, other groups demonstrated the usefulness of 

these ligands in several catalytic asymmetric reactions. 12 

The promising results obtained in the asymmetric hydrogenation 

of N-(1-phenylvinyl)acetamides with enantioselectivities 

of up to 95% ee and catalyst activities up to 

2000 h 1 (TOF) motivated us to explore our ligand library 

4 in the hydrogenation of structurally similar enol carbamates, 

which offer an alternative approach to chiral

1. n-BuLi/ 

TMEDA 

2. Cl 2PNEt 2 

HCl 

alcohols. Pioneering work in the field of enantioselective 

hydrogenation of enol carbamates has been reported by 

Feringa, de Vries and Minnaard et al. who have scored 

enantioselectivities of up to 98% ee with rhodium-catalysts 

containing monodentate phosphoramidites (MonoPhosfamily). 

2.1. Ligand synthesis 

P NEt 2 

2 

2. Results and discussion 

In general, the ligands were prepared by double metallation 

of 2,2 0 -dimethylbinaphthyl 1 with 2 equiv of n-butyl lithium, 

followed by quenching with diethylaminodichlorophosphine 

or with aryl and alkyl dichlorophosphines. 

Deprotection of the diethylamino phosphine 2 with gaseous 

HCl produced 4-chloro-4,5-dihydro-3H-dinaphtho[2,1c;1 

0 ,2 0 -e]phosphepine 3 in 80% yield. This enantiomerically 

pure chlorophosphine is easily coupled with various Grignard 

reagents or organo-lithium compounds to give a broad 

selection of ligands 4. In order to expand the application of 

this class of ligands, we prepared derivatives of 1, bearing 

CH 3 

CH 3 

P Cl 

3 

1 

RMgX 

or RLi 

1. n-BuLi/ 

TMEDA 

2. Cl 2PR 

P R 

4 

4a: R = Ph 

4b: R = p-CF 3C 6H 4 

4c: R = 3,5-(CH 3) 2C 6H 3 

4d: R = p-CH 3OC 6H 4 

4e: R = o-CH 3OC 6H 4 

4f: R = iPr 

4g: R = tBu 

Scheme 1. General synthesis of ligands with 2,2 0 -binaphthyl framework. 

S. Enthaler et al. / Tetrahedron: Asymmetry 18 (2007) 1288–1298 1289 

H 2O 2 

P Ph 

O 

P R 

7 

HSiCl 3 

6' 

5' 4' 

10' 3' 

7 

6 

5 

6 

10 2' 

12' 

7' 

8' 

8 

9' 

9 

1' 11' 

i 

5 11 

2 

4 

3 

12 

o O 

P m 

p 

LDA/MeI 

5a: R = Ph 

5b: R = p-CH 3OC 6H 4 

substituents on the aliphatic carbon at the a-position to 

the phosphorus. The desired bis-methylated product 7 has 

been obtained via a deprotonation–alkylation protocol. 

After the preliminary step of oxidation of 4-phenyl-4,5dihydro-3H-dinaphtho[2,1-c;1 

0 ,2 0 -e]phosphepine 4a with 

H2O2, lithiation and alkylation were performed by the addition 

of LDA (3 equiv) and CH 3I (2 equiv) at room temperature. 

The reaction is completely stereoselective, and only 

one of the possible dialkylated products is obtained 

(Scheme 1). 

Recently, Widhalm et al. reported a similar approach to 

the synthesis of compound 7, via the phosphepine sulfide 

instead of the oxide. 13 To compare the two procedures, 

the stereochemistry of the new stereogenic centres in the 

phosphepine oxide 6 was studied in detail. 

The stereochemistry of compound 6 was confirmed by 

NMR spectroscopy. The initial 31 P NMR measurements 

displayed the occurrence of exclusively one enantiomer 

for 6 and 7 in each case, since only one single signal was 

found and racemization of the binaphthyl backbone over 

the course of reactions was excluded. In a two-dimensional 

Table 1. Selected bond lengths [A˚ ] and angles [°] of the phosphepine oxides 5a, 5b and 6 

5a 6 5b a 

P1–C1 1.812(5) P1–C25 1.799(3) P1–C1 1.824(4) 

[P2–C30] [1.825(4)] 

P1–C7 1.813(4) P1–C22 1.832(2) P1–C29 1.833(4) 

[P2–C58] [1.846(4)] 

P1–C28 1.814(5) P1–C1 1.834(2) P1–C8 1.837(4) 

[P2–C37] [1.819(4)] 

P1–O1 1.481(3) P1–O1 1.483(2) P1–O1 1.444(3) 

[P2–O3] [1.407(5)] 

C7–P1–C1 109.6(2) C25–P1–C22 108.6(1) C1–P1–C29 107.9 (2) 

[C30–P2–C37] [107.2 (2)] 

C28–P1–C1 104.0(2) C25–P1–C1 104.2(1) C1–P1–C8 105.4(2) 

[C30–P2–C58] [103.0(2)] 

C7–P1–C28 103.1(2) C22–P1–C1 108.8 (1) C29–P1–C8 102.3(2) 

[C58–P2–C37] [100.8(2)] 

a 

Values of the second molecule in the asymmetric unit are in brackets.

1290 S. Enthaler et al. / Tetrahedron: Asymmetry 18 (2007) 1288–1298 

Figure 1. ORTEP plot of compounds 5a, 6 and 5b. Hydrogen atoms are omitted for clarity. The thermal ellipsoids correspond to 30% probability. With 

respect to compound 5b, only one of the two symmetry-independent molecules of the asymmetric unit is depicted. 

NOESY spectrum, correlations between the following protons 

were observed: o-Ph with H-3 0 , H-11 0 and Me(12); H-3 

with H-11 and H-3 0 with H-11 0 , respectively, indicating the 

bis-axial orientation of both methyl groups. The spatial 

proximity of the methyl group Me(12) and of the phenyl 

group is also reflected by the difference in 1 H chemical shift 

values of both methyl groups (dMe(12) = 0.61 and 

Me(12 0 ) = 0.95). The high-field shift of the signal for the 

methyl group Me(12) can be explained by the anisotropic 

effect of the phenyl substituent on the phosphorus. 

In addition, useful structural data were gained by X-ray 

crystallography of oxide 6. For comparison, X-ray structure 

analyses of the corresponding unsubstituted systems 

5a and 5b were determined. Selected bond lengths and angles 

are shown in Table 1. The molecular structures of the 

three oxides are given in Figure 1. In the case of 5b, two 

molecules have been found in the asymmetric unit with 

similar structural features. As expected in all compounds 

the substituents show an approximately tetrahedral 

arrangement at the phosphorus atom. The a,a-disubstituted 

phosphepine oxide 6 features shorter exocyclic 

(P1–C25 1.799(3) A ˚ ) than the endocyclic P–C bonds 

(P1–C22 1.832(2) A ˚ and P1–C1 1.834(2) A ˚ ) in comparison 

with the unsubstituted system 5a where all P–C bonds are 

equally long (Table 1). Furthermore, the a,a-substitution 

promotes a pronounced expansion of the endocyclic 

C–P–C angle up to 108.8(1)° (6) from 103.1(2)° (5a). 

In accordance with the NMR studies and the X-ray structure 

analysis, the configuration of compound 6 was assigned 

to be (S,S,Sa). The stereochemistry of ligand 7 was allotted 

in analogy to the one of the corresponding oxide. 

2.2. Catalytic experiments 

The synthesis of enol carbamates 8–14 was carried out in 

analogy to literature protocols, by reacting the corresponding 

ketone with NaH and subsequent addition of the corresponding 

carbamoyl chloride. 5m,14 

Initial studies on the influence of reaction conditions were 

performed with 1-phenylvinyl N,N-diethylcarbamate 8 

as substrate and 4-phenyl-4,5-dihydro-3H-dinaphtho[2,1c;1 

0 ,2 0 -e]phosphepine 4a as our standard ligand. Typically, 

we used an in situ pre-catalytic mixture of 1.0 mol % 

[Rh(cod)2]BF4 and 2.1 mol % of the ligand. All hydrogenation 

reactions were carried out in an eightfold parallel reactor 

array with a 3.0 ml reactor volume. 15 

First we investigated the influence of different solvents, 

such as methylene chloride, methanol, ethanol and 2-propanol 

in combination with a variation of the initial hydrogen 

pressure (1.0, 5.0, 10.0, 25.0 and 50.0 bar). Selected 

results are presented in Figure 2. 

ee [90%] 

100 

O 

90 

80 

70 

60 

50 

40 

30 

20 

10 

0 

N 

O 

8 

1 

5 

[Rh(cod) 2]BF 4 + 2.1 (4a) 

25 °C, 24 h, H 2 

10 

pressure [bar] 

O O 

Surprisingly, by applying toluene as solvent in the hydrogenation 

of enol carbamate 8 no reaction occurred, while 

in previous studies toluene was found to be the solvent of 

choice for the hydrogenation of enamides and a-amino 

acids. 11c,e The best enantioselectivities of up to 96% ee were 

obtained with methanol as solvent with a hydrogen pressure 

of 25 bar. 

Two different pressure-enantioselectivity-dependencies 

have been noticed. In ethanol and 2-propanol, the enantioselectivity 

decreased when increasing the hydrogen pressure 

(1 bar: ethanol: 74% ee, 2-propanol: 74% ee, 50 bar: ethanol: 

25 

50 

N 

CH2Cl2 2-PrOH 

8a 

MeOH 

EtOH 

Figure 2. Solvent and pressure variation. Reactions were carried out at 

25 °C for 24 h with 0.0024 mmol [Rh(cod) 2]BF 4, 0.005 mmol ligand 4a and 

0.24 mmol 8 in 2.0 ml solvent.

64% ee, 2-propanol: 50% ee) whereas in methylene chloride 

and methanol, the reverse behaviour was observed (1 bar: 

methanol: 72% ee, methylene chloride: 66% ee, 50 bar: 

methanol: 92% ee, methylene chloride: 86% ee). With the 

exception of 2-propanol (>99%), moderate to good conversions 

(60–90%) were observed at lower pressures within a 

reasonable time (24 h), while at higher pressure a complete 

conversion was achieved. The results indicated methanol as 

the solvent of choice (conversion: >99%; enantioselectivity: 

96% ee). In addition, in order to estimate the effect of the 

protic solvent on the product structure the reaction was 

performed in methanol-d4. Analysis of the 1 H NMR spectra 

showed that no incorporation of deuterium in the product 

had occurred. Therefore, one can rule out any 

interference of the solvent in the catalytic cycle due to 

transfer hydrogenation and/or protonolysis of Rh-Cspecies. 

16 

In order to assess the optimum reaction conditions, a 

detailed pressure investigation was performed (Fig. 3). 

The results illustrated a constant range of enantioselectivity 

( 74% ee) between initial pressures of 1–18 bar, followed 

by an increase of up to a maximum of 96% ee at 25 bar. 

A further increase in the hydrogen pressure did not result 

in any improvement while enantioselectivities ranged 

between 92% and 94% ee in the region of 30–50 bar. 

ee [%] 

O 

100 

90 

80 

70 

60 

50 

40 

30 

20 

10 

0 

N 

O 

8 

[Rh(cod) 2]BF 4 + 2.1 (4a) 

25 ºC, 24 h, H 2 

O O 

1 5 10 12 15 18 20 25 30 40 50 

pressure [bar] 

Figure 3. Study of pressure-enantioselectivity-dependency. Reactions were 

carried out at 25 °C for 24 h with 0.0024 mmol [Rh(cod)2]BF4, 0.005 mmol 

ligand 4a and 0.24 mmol 8 in 2.0 ml methanol. 

The optimal reaction conditions devised in the solventpressure 

investigation (methanol as solvent and 25 bar as 

initial hydrogen pressure) were applied in a temperature 

study (Fig. 4). With the model ligand 4a in the hydrogenation 

of compound 8, we observed a high stability of the 

enantioselectivity (94–96% ee) in the range of 10–90 °C 

albeit with a reduction of conversion at 90 °C. A further 

increase to 110 °C produced a racemic mixture of 8a, probably 

as a result of ligand degradation. 17 

In order to evaluate the substituent effect at the phosphorus 

atom of the ligand, we studied the model reaction of 1-phen- 


N 

8a 

[%] 

O 

100 

90 

80 

70 

60 

50 

40 

30 

20 

10 

0 

N 

O 

8 

[Rh(cod) 2]BF 4 + 2.1 (4a) 

24 h, H 2 (25 bar) 

O O 

10 30 50 70 90 110 

temperature [˚C] 

ylvinyl N,N-diethylcarbamate 8 in the presence of eight 

different 4,5-dihydro-3H-dinaphtho[2,1-c;1 0 ,2 0 -e]phosphepines 

4a–4g and 7 using the optimized reaction conditions 

(2.5 bar hydrogen pressure, methanol, 30 °C, 6 h). The 

results are presented in Table 2. In the hydrogenation of 

8, the best enantioselectivities of up to 90% and 72% ee, 

respectively, were achieved with ligand 4a and 4d (Table 

2, entries 1 and 4). The presence of electron-donating 

groups, as well as electron-withdrawing groups onto the 

P-aryl substituent, led to a significant decrease of the 

stereoselectivity (Table 1, entries 2–5). 

Catalysts containing alkyl-substituted phosphepines 4f or 

4g gave a significant lower activity and enantioselectivity 

compared to aryl-substituted phosphepines. Interestingly, 

in the case of ligand 4g and 7, the opposite enantiomer is 

formed during the reaction. A similar behaviour of the 

N 

8a 

ee 

conversion 

Figure 4. Dependency of enantioselectivity versus temperature. Reactions 

were carried out at corresponding temperature for 1–24 h with 

0.0024 mmol [Rh(cod) 2]BF 4, 0.005 mmol ligand 4a and 0.24 mmol 8 in 

2.0 ml methanol. 

Table 2. Hydrogenation of compound 8 with different 4,5-dihydro-3Hdinaphtho[2,1-c;1 

0 ,2 0 -e]phosphepines 4a–4g and ligand 7 a 

O 

N 

O 

8 

[Rh(cod) 2]BF 4 + 2.1 (4 or 7) 

MeOH, 6 h, H 2 (25 bar) 

N 

O O 

Entry Ligand Conv. (%) Yield (%) ee (%) 

1 4a >99 >99 96 (S) 

2 4b 40 40 28 (S) 

3 4c >99 >99 66 (S) 

4 4d >99 >99 72 (S) 

5 4e >99 >99 51 (S) 

6 4f 40 40 12 (S) 

7 4g 41 41 50 (R) 

8 b 

7 >99 >99 42 (R) 

a All reactions were carried out at 25 °C under 25 bar pressure of hydrogen 

for 6 h with 0.0024 mmol [Rh(cod)2]BF4, 0.005 mmol ligand and 

0.24 mmol 8 in methanol (2.0 ml). 

b 24 h. 

8a


tert-butyl ligand 4g was previously reported for other 

asymmetric hydrogenations. 11c,f 

To explore the scope and limitation of our ligand toolbox, 

the asymmetric hydrogenation of a range of enol carbamates 

was performed under optimized conditions (Tables 

3 and 4). First the influence of the substitution at the carbamoyl-nitrogen 

was investigated (Table 3). 

Table 3. Variation of the protecting group in the substrate moiety a 

R1 R2 N 

O 

O 

[Rh(cod) 2]BF 4 + 2.1 (4 and 7) 

9: R 1=R 2=Me 

10: R 1=Me R 2=Ph 

11: R 1=Ph R 2=Ph 

MeOH, 24 h, H 2 (25 bar) 

R1 R2 N 

O O 

9a-11a 

Entry Ligand R1 R2 Conv. (%) Yield (%) ee (%) 

1 4a Me Me >99 >99 68 (S) 

2 4b Me Me 33 33 26 (S) 

3 4c Me Me 87 87 65 (S) 

4 4d Me Me >99 >99 75 (S) 

5 4e Me Me 99 99 40 (S) 

6 4f Me Me 26 26 17 (S) 

7 4g Me Me 44 44 33 (R) 

8 7 Me Me 80 80 27 (R) 

9 4a Me Ph >99 >99 58 (S) 

10 4b Me Ph 98 98 37 (S) 

11 4c Me Ph >99 >99 61 (S) 

12 4d Me Ph >99 >99 65 (S) 

13 4e Me Ph >99 >99 42 (S) 

14 4f Me Ph 53 53 4 (S) 

15 4g Me Ph >99 >99 45 (R) 

16 7 Me Ph >99 >99 53 (R) 

17 4a Ph Ph >99 88 10 (S) 

18 4b Ph Ph 98 77 Rac 

19 b 

4c Ph Ph 89 75 41 (S) 

20 4d Ph Ph >99 87 11 (S) 

21 4e Ph Ph >99 87 55 (S) 

22 4f Ph Ph 98 62 4 (S) 

23 4g Ph Ph >99 98 70 (R) 

24 7 Ph Ph >99 98 76 (R) 

a All reactions were carried out at 25 °C under 25 bar pressure of hydrogen 

for 24 h with 0.0024 mmol [Rh(cod) 2]BF 4, 0.005 mmol ligand and 

0.24 mmol substrate in methanol (2.0 ml). 

b Reaction was carried out for 6 h. 

All substrates were hydrogenated under the optimized conditions 

with eight different ligands 4a–4g and 7. The enol 

carbamates 9–11 undergo the reaction with good conversion 

in most cases (Table 3). The negative influence on 

the activity was again observed by the electron-withdrawing 

substituent on the phenyl (entries 2, 10 and 18) and 

by the alkyl group on the phosphorus, mainly i-Pr (Table 

3, entries 6, 7, 14 and 22). On the other hand in some cases 

a positive effect on the selectivity by substitution with electron 

donating groups was observed (Table 3, entries 4 and 

12). Again the stereoselectivity was reversed in the case of 

ligand 7 and 4g, with 7 being the higher inducer of chirality 

for system 11. The overall results for the three substrates 

9–11 are comparable, showing little influence of the differ- 

ent substituents on the carbamoyl nitrogen on the reaction 

path. 

Finally, the sensitivity on the variations in the double bond 

was investigated. Table 4 summarizes the results for three 

substrates with different substitutions: substitution of the 

phenyl-group by an alkyl-group 14, substitution in the 2position 

of the 1,1-olefin 12 and a cyclic substrate 13. Substrate 

Z-12 was hydrogenated with excellent conversion 

and good enantioselectivity by ligand 4d, while 13, which 

is structurally related to the E-isomer of substrate 12, fails 

to be hydrogenated with all the ligands but exceptionally 

ligand 7 (Table 4, entry 8). The alkyl enol carbamate 14 

is best hydrogenated by ligands 4a and 7, again leading 

to an inversion of enantioselectivity with ligand 7. In general 

the behaviour of substrates 12 and 14 is comparable 

to that of the previous enol carbamates. 

Table 4. Variations of the substituent in the olefin a 

3. Conclusions 

Monodentate phosphine ligands based on a 4,5-dihydro- 

3H-dinaphtho[2,1-c;1 0 ,2 0 -e]phosphepines structure 4 and 7 

have been successfully exploited in the rhodium-catalyzed 

asymmetric hydrogenation of various enol carbamates. 

The influences of different reaction parameters have been 

investigated. For the first time in this reaction a high 

enantioselectivity (up to 96% ee) was obtained in the presence 

of monodentate phosphines. 

4.1. General 

N 

O O 

12 

O O 

4. Experimental 

1 H, 13 C and 31 P NMR spectra were recorded on Bruker 

Spectrometer AVANCE 500, 400 and 300 ( 1 H: 500.13 

MHz, 400.13 MHz and 300.13 MHz; 13 C: 125.8 MHz, 

100.6 MHz and 75.5 MHz; 31 P: 162.0 MHz). The calibration 

N 

13 

N 

O O 

Entry Lig. 12a 13a 14a 

Conv. 

(%) 

ee b 

(%) 

Conv. 

(%) 

ee 

(%) 

14 

Conv. 

(%) 

ee 

(%) 

1 4a 94 50 (S) 99 48 

2 4b 10 12 (R)

of 1 H and 13 C spectra was carried out on solvent signals 

(d(CDCl3) = 7.25 and 77.0). The 31 P chemical shifts are 

referenced to 85% H3PO4. Mass spectra were recorded on 

an AMD 402 spectrometer. Optical rotations were 

measured on a Gyromat-HP polarimeter. IR spectra were 

recorded as KBr pellets or Nujol mulls on a Nicolet Magna 

550. All manipulations with air sensitive compounds were 

performed under argon atmosphere using standard 

Schlenk techniques. Toluene was distilled from sodium 

benzophenone ketyl under argon. Methanol was distilled 

from Mg under argon. Ethanol and 2-propanol were 

distilled from Na under argon. Methylene chloride was distilled 

from CaH2 under argon. Dimethyl sulfoxide (on 

molecular sieves) and [Rh(cod)2]BF4 were purchased from 

Fluka and used without further purifications. Ligands 4 

were synthesized according to our previously published 

protocols. 11 

4.2. Synthesis of ligands 

4.2.1. (S)-4-Phenyl-4,5-dihydro-3H-dinaphtho[2,1-c:10 ,20-e] phosphepine oxide 5a. Ligand 4a (1.5 g, 3.86 mmol) were 

dissolved in acetone (10 ml) and 7.7 ml of 10% sol. H2O2 (23 mmol) were added carefully, cooling with ice-bath. 

After few minutes stirring at room temperature, the solution 

was refluxed at 100 °C for 1 h. The solvent was evaporated 

and the resulting yellow oil taken up with CH2Cl2 

and dried over MgSO4. Purification by column chromatography 

(eluent: ethyl acetate/petroleum ether 4:1) yielded 

1.17 g (75%) of white solid. Mp: 167–168 °C. 1 HNMR 

(500 MHz, CDCl3) d = 8.02 (d, 1H, 3 J3,4 = 8.5 Hz, H-4); 

7.96, 7.95 (2d, 2H, 3 J5,6 = 8.2 Hz, 3J 0 0 

5 ;6 ¼ 8:2 Hz, H-5, 

H-50 ); 7.90 (d, 1H, 3J 0 0 

3 ;4 ¼ 8:5 Hz, H-40 ); 7.70 (d, 1H, 

3 

J3,4 = 8.5 Hz, H-3); 7.53–7.35 (m, 7H, H-6, H-60 , Ph); 

7.29–7.21 (m, 3H), 7.16 (d, 1H, 3 J = 8.5 Hz, H-7, H-70 , 

H-8, H-80 ); 7.21 (d, 1H, 3J 0 0 

3 ;4 ¼ 8:5 Hz, H-30 ); 3.36 (dd, 

1H, 2 JH,H = 14.2 Hz, 2 JP,H = 8.2 Hz, H-11a); 3.32 (dd, 

1H, 2 JP,H = 22.5 Hz, 2 JH,H = 14.2 Hz, H-110a); 3.22 (dd, 

1H, 2 JH,H = 14.2 Hz, 2 JP,H = 13.0 Hz, H-11b); 3.21 (dd, 

1H, 2 JP,H = 16.0 Hz, 2 JH,H = 14.2 Hz, H-110b). 13 CNMR 

(125.8 MHz, CDCl3): d = 134.0 (d, J = 4.0 Hz), 133.4 (d, 

J = 4.0 Hz), 133.0 (d, J = 1.8 Hz), 132.9 (d, J = 1.8 Hz), 

132.4 (d, J = 2.5 Hz), 132.2 (d, J = 1.8 Hz), 130.4 (d, 

J = 8.2 Hz), 129.6 (d, J = 10.0 Hz, C-1, C-10 , C-2, C-20 , 

C-9, C-90 , C-10, C-100 ); 132.1 (d, J = 2.5 Hz, p-Ph); 132.0 

(d, J = 88.0 Hz, i-Ph); 130.9 (d, J = 8.5 Hz, o-Ph); 129.4 

(d, J = 1.8 Hz, C-4); 128.6 (d, J = 1.8 Hz, C-40 ); 128.5 (d, 

J = 11.0 Hz, m-Ph); 128.5 (d, J = 3.5 Hz, C-3); 128.4, 

128.2 (C-5, C-50 ); 128.3 (d, J = 4.5 Hz, C-30 ); 127.1, 

126.7, 126.5, 126.3 (C-7, C-70 , C-8, C-80 ); 125.9 (C-6); 

125.6 (C-60 ); 37.4 (d, J = 65.0 Hz, C-110 ); 36.0 (d, 

J = 64.0 Hz, C-11). 

31 P NMR (121.5 MHz, CDCl3) 

d = 54.0. IR (KBr, cm 1 ): 3052 m; 3008 w; 2951 w; 1618 

w; 1592 w; 1508 m; 1435 m; 1405 m; 1359 w; 1328 w; 

1251 m; 1221 s; 1199 m; 1159 m; 1114 m; 1102 m; 1061 

w; 1026 w; 998 w; 973 w; 960 w; 931 w; 884 w; 866 w; 

836 s; 833 m; 820 s; 802 w; 770 m; 752m; 742 s; 726 w; 

713 w; 703 m; 694 m; 672 w; 661 m; 622 m; 586 w; 568 

w; 544 m; 523 m; 496 w; 470 m; 436 w; 424 w. MS (ESI): 

m/z (%) = 404 ([M + ], 100); 365 (6); 266 (34); 202 (4); 139 

(4); 73 (7). HRMS calcd for C28H21O1P: 404.13245, found: 

404.132628. ½aŠ 22 

D ¼þ79:0 (c 0.46, CHCl3). Retention time: 


64.6 min (30 m HP Agilent Technologies 50-8-260/5-8-280/ 

5-8-300/5). 

4.2.2. (S)-4-(4-Methoxy)phenyl-4,5-dihydro-3H-dinaphtho- 

[2,1-c:10 ,20-e]phosphepine oxide 5b. (S)-4-(4-Methoxy)phenyl-4,5-dihydro-3H-dinaphtho[2,1-c:10 

,20-e]phosphepine 4d (4.2 mmol) was dissolved in acetone (15 ml) and a mixture 

of water (1.1 ml) and 35% sol. H2O2 (5.0 mmol) was 

added carefully. After stirring for 4 h at room temperature, 

the solvent was evaporated and the residue dissolved in 

dichloromethane. The organic phase was washed with 

water, brine and dried over MgSO4. The solvent was 

removed to obtain an off-white foam. Yield: 99%. Mp: 

112–115 °C. 1 H NMR (300 MHz, CDCl3) d = 8.03–7.89 

(m, 4H); 7.69 (dd, 1H, J = 8.5 Hz, J = 1.2 Hz); 7.51–7.41 

(m, 2H); 7.40–7.31 (m, 2H, C6H4); 7.29–7.15 (m, 5H); 

6.89 (m, 2H, C6H4); 3.83 (s, 3H, OMe); 3.37–3.12 

(m, 4H, CH2). 13 C NMR (75.5 MHz, CDCl3) d = 162.5 

(d, J = 3.0 Hz, C6H4); 133.9 (d, J = 3.8 Hz); 133.5 (d, 

J = 3.8 Hz); 132.9 (d, J = 2.0 Hz); 132.7 (d, J = 2.0 Hz); 

132.7 (d, J = 10.2 Hz, C6H4); 132.4 (d, J = 2.5 Hz); 132.1 

(d, J = 2.0 Hz); 130.6 (d, J = 8.2 Hz); 129.8 (d, 

J = 9.5 Hz); 129.3 (d, J = 1.8 Hz); 128.6 (d, J = 1.8 Hz); 

128.4 (d, J = 3.8 Hz); 128.4; 128.3 (d, J = 4.5 Hz); 128.2; 

127.1; 126.7; 126.5; 126.3; 125.8; 125.6; 123.0 (d, 

J = 93.5 Hz, C6H4); 114.0 (d, J = 12.0 Hz, C6H4); 55.3 

(OMe); 37.7 (d, J = 66.0 Hz, CH2); 36.3 (d, J = 64.2 Hz, 

CH2). 31 P NMR (121.5 MHz, CDCl3) d = 54.1. IR (KBr, 

cm 1 ): 3053 m; 2957 w; 2836 w; 1596 s; 1569 w; 1503 s; 

1460 m; 1441 m; 1407 m; 1294 m; 1255 s; 1217 m; 1178 s; 

1117 s; 1027 m; 931 w; 871 w; 816 s; 744 m; 684 w; 660 

w; 623 w; 567 w; 544 m; 527 m; 496 w; 457 w; 419 w. 

MS (EI): m/z (%) = 434 ([M + ], 100); 282 (20); 279 (37); 

266 (32); 121 (27). HRMS calcd for C29H23O2P: 

434.14302, found: 434.142805. ½aŠ 22 

D ¼ 293 (c 0.25, 

CHCl3). 

4.2.3. (S,S,Sa)-3,5-Dimethyl-4-phenyl-4,5-dihydro-3H-dinaphtho[2,1-c:1 

0 ,2 0 -e]phosphepine oxide 6. Phosphepine 

oxide 5 (1.37 g, 3.4 mmol) is dissolved in 14 ml of THF, 

followed by the addition of 0.42 ml (6.8 mmol) of methyl 

iodide. To the well stirred solution, 22 ml of LDA 

(11 mmol, 0.5 M) are added slowly at room temperature. 

The dark red solution was stirred for 1 h and afterwards 

quenched with few drops of water. The solvents were evaporated 

under reduced pressure. The product was taken up 

with 50 ml of CH2Cl2, washed with 50 ml of H2O and the 

water phase extracted with CH2Cl2 (2 · 50 ml). The organic 

phases are dried over MgSO 4 and the solvents evaporated, 

yielding 1.45 g of light yellow foam. Purification by 

column chromatography on SiO2, eluting with acetone/ 

petroleum ether 1:1 yielded 0.56 g (38%) of a white solid. 

Mp: 292–305 °C. 1 H NMR (500 MHz, CDCl3) d = 8.02 

(d, 1H, 3 J 3 0 ;4 0 ¼ 8:5 Hz, H-4 0 ); 7.97 (d, 1H, 3 J3,4 = 8.5 Hz, 

H-4); 7.95 (d, 1H, 3 J5,6 = 8.2 Hz, H-5); 7.92 (d, 1H, 

3 J 5 0 ;6 0 ¼ 8:2 Hz, H-5 0 ); 7.72–7.68 (m, 2H, o-Ph); 7.65 (d, 

1H, 3 J3,4 = 8.5 Hz, H-3); 7.55 (d, 1H, 3 J 3 0 ;4 0 ¼ 8:5 Hz, H- 

3 0 ); 7.50–7.39 (m, 5H, H-6, H-6 0 , m-, p-Ph); 7.24–7.18 (m, 

3H), 7.05 (d, 1H, 3 J = 8.5 Hz, H-7, H-7 0 , H-8, H-8 0 ); 3.62 

(m, 1H, 2 JP,H = 15.0 Hz, 3 J 11 0 ;12 0 ¼ 7:7 Hz, H-11 0 ); 3.43 

(dq, 1H, 2 JP,H = 22.0 Hz, 3 J11,12 = 7.7 Hz, H-11); 0.95 

(dd, 1H, 3 J P,H = 14.0 Hz, 3 J 11 0 ;12 0 ¼ 7:7 Hz, H-12 0 ); 0.61


3 JP,H = 16.1 Hz, 

3 J11,12 = 7.7 Hz, H-12). 

13 C 

(dd, 1H, 

NMR (125.8 MHz, CDCl3): d = 135.2 (d, J = 3.2 Hz, C- 

10 ); 134.5 (d, J = 5.0 Hz, C-20 ); 134.0 (d, J = 7.0 Hz, C-2); 

133.9 (d, J = 3.0 Hz), 133.8 (d, J = 1.8 Hz), 133.4 (d, 

J = 1.8 Hz), 133.0 (d, J = 1.5 Hz), 132.8 (d, J = 1.5 Hz, 

C-1, C-9, C-90 , C-10, C-100 ); 133.2 (d, J = 83.0 Hz, i-Ph); 

131.7 (d, J = 2.5 Hz, p-Ph); 131.1 (d, J = 8.2 Hz, o-Ph); 

130.1 (d, J = 5.0 Hz, C-3); 129.3 (d, J = 6.8 Hz, C-30 ); 

129.2 (C-4); 129.1 (C-40 ); 128.2, 128.0 (C-5, C-50 ); 128.2 

(d, J = 10.0 Hz, m-Ph); 127.0, 126.6, 126.5, 126.3 (C-7, C- 

70 , C-8, C-80 ); 126.1 (C-6); 125.7 (C-60 ); 46.4 (d, 

J = 59.5 Hz, C-11); 43.2 (d, J = 63.0 Hz, C-110 ); 17.0 (C- 

12); 14.6 (d, J = 4.5 Hz, C-120 ). 31 P NMR (121.5 MHz, 

CDCl3) d = 51.3. IR (KBr, cm 1 ): 3039 m; 2990 m; 2931 

m; 2874 w; 1618 w; 1594 m; 1568 w; 1504 m; 1455 w; 

1436 m; 1375 w; 1341 w; 1325 w; 1292 w; 1253 m; 1225 

w; 1184 m; 1166 s; 1112 m; 1092 m; 1057 m; 1028 w; 999 

w; 957 w; 915 w; 896 m; 871 w; 838 m; 820 s; 796 w; 768 

w; 756 m; 739 s; 711 m; 704 m; 689 m; 667 s; 632 w; 583 

w; 564 s; 534 m; 520 w; 509 w; 482 m; 459 m; 418 w; 403 

w. MS (ESI): m/z (%) = 432 ([M + ], 44); 417 (2); 388 (2); 

360 (1); 328 (2); 293 (15); 278 (100); 265 (15); 231 (4); 208 

(12); 179 (2); 145 (16); 132 (33); 77 (7); 47 (4). HRMS calcd 

for C30H25OP: 432.16375, found: 432.163562. ½aŠ 22 

D ¼þ93:5 

(c 0.25, CHCl3). Retention time: 58.6 min (30 m HP Agilent 

Technologies 50-8-260/5-8-280/5-8-300/5). 

4.2.4. (S,S,Sa)-3,5-Dimethyl-4-phenyl-4,5-dihydro-3H-dinaphtho[2,1-c:10 

,20-e]phosphepine 7. Phosphepine oxide 6 

(0.08 g, 0.2 mmol) was dissolved in dry toluene (6 ml) 

and triethylamine (0.2 ml, 1.4 mmol) was added to the 

solution. The mixture was cooled to 0 °C with an ice-bath 

and HSiCl3 (0.1 ml, 1 mmol) was added. After the addition 

was complete, the solution was refluxed for 4 h. The reaction 

was quenched by 5 ml basic aqueous solution, and 

the aqueous phase washed with toluene (2 · 5 ml). The 

organic phase was dried over Na2SO4 and the solvent 

evaporated under reduced pressure. Yield 70 mg (91%). 

Mp: 212 °C. 1 H NMR (300 MHz, CDCl3) d = 8.04–7.90 

(m, 4H); 7.73–7.63 (m, 3H); 7.55 (d, 1H, J = 8.5 Hz); 

7.51–7.38 (m, 5H); 7.26–7.16 (m, 3H); 7.06 (d, 1H, J = 

8.5 Hz); 3.62 (m, 1H, 2 JP,H = 15.5 Hz, 3 JH,Me = 7.5 Hz, 

CHMe); 3.43 (dq, 1H, 2 JP,H = 22.0 Hz, 3 JH,Me = 7.5 Hz, 

CHMe); 0.95 (dd, 3H, 3 JP,H = 13.9 Hz, 3 JH,Me = 7.5 Hz, 

Me); 0.61 (dd, 3H, 3 JP,H = 16.0 Hz, 3 JH,Me = .5 Hz, Me). 

13 

C NMR (75.5 MHz, CDCl3) d = 141.2 (d, J = 2.5 Hz); 

138.5 (d, J = 1.0 Hz); 138.5 (d, J = 25.8 Hz); 134.7 (d, 

J = 5.8 Hz); 134.3; 133.9; 133.86 (d, J = 2.8 Hz); 132.8 (d, 

J = 19.5 Hz); 132.7; 132.2; 128.9 (d, J = 3.0 Hz); 128.8; 

128.6 (d, J = 1.0 Hz); 128.4; 128.3 (d, J = 3.2 Hz); 128.2; 

128.1; 127.9; 126.6; 126.5; 126.0; 126.0; 125.2; 125.1; 39.3 

(d, J = 20.0 Hz, CHMe); 36.6 (d, J = 20.0 Hz, CHMe); 

22.3 (d, J = 35.5 Hz, Me); 14.0 (d, J = 3.5 Hz, Me). 31 P 

NMR d = 31.46 (s). MS (ESI): m/z (%): 416 ([M + ], 100), 

360 (10), 265 (38), 149 (9). HRMS: calcd for C30H25P 

416.16884, found: 416.167881. ½aŠ 25 

D ¼þ87:5 (c 0.2, 

CHCl3). 

4.3. General synthesis of enol carbamate derivates 8–14 14,5m 

A solution of sodium hydride (0.11 mol) in dry dimethyl 

sulfoxide (200 ml) was stirred for 2 h at 50 °C under an 

atmosphere of argon. The grey suspension was added dropwise 

to the corresponding ketone (0.1 mol) in 25 ml of dimethyl 

sulfoxide at room temperature. The orange 

solution was stirred for 15 min at room temperature and 

then cooled to 10 °C. The addition of the corresponding 

carbamoyl chloride (0.11 mol) in dimethyl sulfoxide 

(0.11 mol) was carried out in 30 min while maintaining 

the temperature at 10 °C. After stirring overnight at room 

temperature, the solution was carefully quenched with 

water (250 ml), extracted with n-hexane or heptane 

(3 · 250 ml), washed with brine (250 ml) and dried over 

MgSO4 or Na2SO4. The solvents were removed in vacuo 

and the obtained yellow oil purified by column chromatography 

or crystallization. 

4.3.1. 1-Phenylvinyl N,N-diethylcarbamate 8. Purification 

by column chromatography (eluent: ethylacetate/n-hexane 

1 

1:10) yielded a yellow oil. Yield: 18%. H NMR 

(300 MHz, CDCl3) d = 7.44–7.39 (m, 2H, Ph); 7.30–7.19 

(m, 3H, Ph); 5.35 (d, 1H, J = 2.0 Hz, @CH2); 4.96 (d, 

1H, J = 2.0 Hz, @CH2); 3.35 (q, 2H, J = 7.0 Hz, CH2); 3.25 (q, 2H, J = 7.0 Hz, CH2); 1.20 (t, 3H, J = 7.0 Hz, 

13 

CH3); 1.10 (t, 3H, J = 7.0 Hz, CH3). C NMR 

(75.5 MHz, CDCl3) d = 153.8; 153.4; 135.2; 128.6; 128.4; 

124.8; 101.3; 42.0; 41.7; 14.3; 13.3. IR (KBr, cm 1 ): 

3059 w; 3027 w; 2975 m; 2934 m; 2876 w; 1719 s; 1641 

m; 1600 w; 1577 w; 1495 m; 1474 m; 1457 m; 1420 s; 

1380 m; 1351 w; 1314 w; 1255 s; 1225 m; 1158 s; 1097 m; 

1076 m; 1050 m; 1027 w; 981 w; 902 w; 869 m; 787 m; 

771 m; 759 m; 703 m; w; 638 w; 578 w. MS (ESI): m/z 

(%) = 219 ([M + ], 9); 103 (12); 100 (100); 77 (16); 72 (72); 

44 (16). HRMS calcd for C13H17O2N: 219.1254, found: 

219.1253. Retention time: 17.8 min (30 m HP Agilent 

Technologies 50-8-260/5-8-280/5-8-300/5). 

4.3.2. 1-Phenylvinyl N,N-dimethylcarbamate 9. Purification 

by column chromatography on silica gel eluting with 

hexane/ethyl acetate 4:1 yielded 6.4 g of an orange oil. 

Yield: 34%. 1 H NMR (300 MHz, CDCl3) d = 7.48–7.28 

(m, 5H, Ph); 5.41 (1H, d, J = 2.0 Hz, @CH 2); 5.02 (d, 

1H, J = 2.0 Hz, @CH2); 3.10 (s, 3H, CH3); 2.96 (s, 3H, 

CH3). 13 C NMR (75.5 MHz, CDCl3) d = 154.5; 153.4; 

135.1; 128.7; 128.5; 124.9; 101.6; 36.7; 36.4. IR (KBr, 

cm 1 ): 3084 w, 3058 w, 3023 w, 2934 m, 1958 w, 1724 s, 

1643 m, 1601 w, 1577 m, 1494 s, 1445 s, 1391 s, 1313 m, 

1295 m, 1262 s, 1168 s, 1098 m, 1076 m, 1030 m, 928 m, 

875 m, 858 m, 772 s, 759 m, 708 m, 692 m, 641 w, 581 w. 

MS (ESI): m/z (%) = 191 ([M + ], 12); 103 (4); 91 (4); 77 

(7); 72 (100); 51 (5). HRMS calcd for C11H13O2N: 

191.09408, found: 191.09370. Retention time: 16.8 min 

(30 m HP Agilent Technologies 50-8-260/5-8-280/5-8-300/ 

5). 

4.3.3. 1-Phenylvinyl N-methyl N-phenylcarbamate 10. 

Purification by column chromatography on silica gel eluting 

with n-hexane/ethyl acetate 1:1 followed by crystallization 

with acetone/diethylether/n-hexane 1:2:4. Yield: 25%. 

Mp: 56–59 °C. 1 H NMR (300 MHz, CDCl3) d = 7.42– 

7.26 (m, 10H, Ph); 5.39 (1H, d, J = 1.7 Hz, @CH 2); 5.06 

(d, 1H, J = 1.7 Hz, @CH2); 3.38 (br s, 3H, CH3). 13 C 

NMR (75.5 MHz, CDCl3) d = 153.6; 153.4; 143.0; 134.9; 

129.2; 128.8; 128.4; 126.7 (br); 126.0 (br); 125.0; 101.6;

38.3. IR (KBr, cm 1 ): 3762 w; 3407 w; 3119 w; 3085w; 3067 

w; 3037 w; 2975 w; 2937 w; 2557 w; 1966w; 1891 w; 1813 w; 

1717 s; 1643 m; 1592 m; 1578 w; 1493 s; 1446 m; 1420 m; 

1370 s; 1294 m; 1257 s; 1180 w; 1146 s; 1088 m; 1072 m; 

1050 w; 1025 m; 1004 w; 981 m; 916 w; 875 m; 840 w; 

827 w; 771 m; 754 m; 705 s; 687 m; 602 w; 588 m; 563 w; 

529 w; 429 w; 408 m. MS (ESI): m/z (%) = 253 ([M + ], 4); 

134 (100); 119 (4); 106 (37); 91 (6); 77 (38); 65 (4); 51 

(10); 39 (3). HRMS calcd for C16H15O2N: 253.10973, 

found: 253.10977. Retention time: 23.1 min (30 m HP Agilent 

Technologies 50-8-260/5-8-280/5-8-300/5). 

4.3.4. 1-Phenylvinyl N,N-diphenylcarbamate 11. Crystallization 

from acetone/diethylether/n-hexane 1:2:5 yielded 

white-greenish crystals. Yield: 38%. Mp: 72–75 °C. 1 H 

NMR (300 MHz, CDCl3) d = 7.26–7.21 (m, 15H, Ph); 

5.40 (1H, d, J = 2.2 Hz, @CH 2); 5.14 (1H, d, J = 2.2 Hz, 

@CH2). 13 C NMR (75.5 MHz, CDCl3) d = 153.2; 152.5; 

142.2; 134.7; 129.1; 128.8; 128.4; 126.8; 126.5; 125.0; 

101.6. IR (KBr, cm 1 ): 3088 w; 3057 m; 1952 w; 1879 w; 

1801 w; 1721 s; 1646 m; 1590 m; 1492 s; 1451 m; 1384 w; 

1347 s; 1328 m; 1307 m; 1293 m; 1256 s; 1201 s; 1184 m; 

1172 m; 1097 m; 1078 m; 1044 m; 1032 m; 1024 m; 913 

w; 870 m; 836 w; 770 s; 761 s; 694 s; 638 m; 620 w; 597 

m; 566 w; 530 m; 512 m; 443 w; 412 w. MS (ESI): m/z 

(%) = 315 ([M + ], 13); 196 (100); 168 (46); 103 (17); 91 (4); 

77 (22); 51 (7). HRMS calcd for C 21H 17O 2N: 315.12538, 


Technologies 50-8-260/5-8-280/5-8-300/5). 

4.3.5. (Z)-1-Phenylprop-1-enyl N,N-diethylcarbamate 12. 18 

Colourless oil was obtained after column chromatography 

(eluent: ethyl acetate/n-hexane 1:10). Yield: 38%. 1 H NMR 

(500 MHz, CDCl3) d = 7.40 (m, 2H, o-Ph); 7.30 (m, 2H, m- 

Ph); 7.23 (m, 2H, p-Ph); 5.85 (q, 1H, 3 J1,2 = 7.0 Hz, H-2); 

3.49, 3.36 (2q, 4H, H-5, H-5 0 ); 1.74 (d, 3H, 3 J1,2=7.0 Hz, 

H-1); 1.29, 1.17 (2t, 6H, 3 J 5,6 = 7.0 Hz, 3 J 5 0 ;6 0 ¼ 7:0 Hz, 

H-6, H-6 0 ). 13 C NMR (125.8 MHz, CDCl3) d = 153.4 

(C@O); 147.3 (C–O); 136.0 (i-Ph); 128.3 (m-Ph); 127.6 (p- 

Ph); 124.3 (o-Ph); 112.4 (C-2); 42.1, 41.7 (C-5, C-5 0 ); 

14.4, 13.4 (C-6, C-6 0 ); 11.4 (C-1). IR (KBr, cm 1 ): 3058 

w; 2975 m; 2934 m; 2875 w; 1717 s; 1673 m; 1600 w; 

1577 w; 1495 m; 1474 m; 1458 m; 1420 s; 1380 m; 1351 

w; 1313 m; 1258 s; 1225 m; 1158 s; 1116 m; 1097 m; 1061 

m; 1033 w; 1006 m; 972 w; 951 w; 926 w; 851 w; 793 w; 

753 s; 692 m; 652 w; 637 w; 574 w. MS (ESI): m/z 

(%) = 233 ([M + ], 6); 115 (9); 105 (8); 100 (100); 77 (12); 

72 (52); 44 (12). HRMS calcd for C14H19O2N: 233.14103, 


Technologies 50-8-260/5-8-280/5-8-300/5). Retention 

time (HPLC): 8.72 min (eluent: n-hexane/ethanol 98:2; 

flow: 1.0 ml/min). 

4.3.6. 1H-Inden-3-yl N,N-diethyl carbamate 13. An 

orange oil was obtained after column chromatography 

(eluent: ethyl acetate/n-hexane 1:10). Yield: 58%. 1 H 

NMR (300 MHz, CDCl3) d = 7.34–7.10 (m, 4H); 6.19 (t, 

1H, J = 2.3 Hz, CH); 3.41–3.27 (m, 4H, CH2CH3); 3.29 

(d, 2H, J = 2.3 Hz, CH 2CH); 1.22–1.08 (m, 6H, CH 3). 

13 C NMR (75.5 MHz, CDCl3) d = 153.0; 149.4; 141.9; 

139.7; 126.1; 125.4; 124.0; 117.8; 113.6; 42.3; 42.1; 34.8; 

14.3; 13.4. IR (KBr, cm 1 ): 3074 w; 3024 w; 2975 m; 


2934 m; 2890 m; 1726 s; 1653 w; 1616 m; 1605 m; 1577 

m; 1474 m; 1459 m; 1420 s; 1380 m; 1361 m; 1316 m; 

1267 s; 1235 m; 1223 m; 1204 m; 1172 s; 1156 s; 1118 m; 

1098 m; 1076 m; 1017 w; 973 m; 953 m; 932 m; 915 w; 

844 w; 761 s; 717 m; 635 w; 593 w; 553 w; 511 w; 467 w; 

412 w. MS (ESI): m/z (%) = 231 ([M + ], 6); 131 (10); 115 

(6); 103 (11); 100 (100); 77 (14); 72 (62); 44 (17). HRMS 

calcd for C 14H 17O 2N: 231.12538; Found: 231.124840. 

Retention time: 21.3 min (30 m HP Agilent Technologies 

50-8-260/5-8-280/5-8-300/5). 

4.3.7. 3,3-Dimethylbut-1-en-2-yl N,N-diethyl carbamate 14. 

A colourless oil was obtained after column chromatography 

(eluent: ethyl acetate/n-hexane 1:3). Yield: 27%. 1 H 

NMR (400 MHz, CDCl3) d = 4.76 (d, 1H, J = 1.9 Hz, 

@CH2); 4.64 (d, 1H, J = 1.9 Hz, @CH2); 3.31 (q, 4H, 

J = 7.0 Hz, CH2CH3); 1.16–1.12 (br, 6H, CH2CH3); 1.10 (s, 9H, CH3). 

13 C NMR (100.6 MHz, CDCl3) 

d = 163.0; 154.1; 96.2; 42.0; 41.6; 36.2; 27.9; 14.2; 13.4. 

IR (KBr, cm 1 ): 3125 w; 2973 s; 2936 m; 2876 m; 1720 s; 

1653 m; 1555 w; 1506 w; 1474 m; 1461 m; 1419 s; 1380 

m; 1362 m; 1317 m; 1264 s; 1225 m; 1148 s; 1097 m; 1054 

m; 979 m; 938 w; 859 m; 786 m; 756 m; 703 w; 655 w; 

593 w; 488 w. MS (ESI): m/z (%) = 199 ([M + ], 1); 118 

(1); 100 (100); 85 (2); 72 (50); 67 (3); 55 (5); 44 (15). HRMS 

calcd for C11H21O2N: 199.15668, found: 199.155983. 

Retention time: 11.5 min (30 m HP Agilent Technologies 

50-8-260/5-8-280/5-8-300/5). 

4.4. General procedure for the catalytic hydrogenation of 

enol carbamates 

The catalyst was generated in situ by stirring [Rh(cod) 2]- 

BF4 (0.0024 mmol) and the corresponding 4,5-dihydro- 

3H-dinaphthophosphepines ligand (0.005 mmol) in 1.0 ml 

of solvent for a period of 10 min and afterwards transferring 

via syringe into the autoclave. A solution of the enol 

carbamate (0.24 mmol) and 1.0 ml solvent was transferred 

via syringe into the autoclave. Then, the autoclave was 

charged with hydrogen and stirred at the required temperature. 

After a predetermined time the hydrogen was released 

and the reaction mixture passed through a short 

plug of silica gel. The conversion and enantioselectivity 

were measured by GC and HPLC without further 

modifications. 

4.4.1. 1-Phenylethyl N,N-diethylcarbamate 8a. Colourless 

oil. 1 H NMR (300 MHz, CDCl3) d = 7.31–7.11 (m, 5H, 

Ph); 5.73 (d, 1H, J = 6.5 Hz, CH); 3.20 (q, 4H, 

J = 7.0 Hz, CH2); 1.44 (d, 3H, J = 6.5 Hz, CH3); 1.02 (t, 

6H, J = 7.0 Hz, CH3). 13 C NMR (75.5 MHz, CDCl3) 

d = 155.1; 142.6; 128.2; 127.3; 125.7; 72.6; 41.5; 41.1; 

22.7; 14.0; 13.4. IR (KBr, cm 1 ): 3087 w; 3064 w; 3033 

w; 2977 s; 2933 m; 2875 w; 1700 s; 1630 m; 1586 w; 1539 

w; 1495 m; 1476 s; 1457 s; 1425 s; 1379 m; 1316 m; 2174 

s; 1227 m; 1210 m; 1172 s; 1069 s; 1030 m; 1010 m; 998 

m; 973 m; 940 w; 911 w; 877 w; 787 m; 766 m; 700 s; 630 

w; 576 w; 535 m. MS (ESI): m/z (%) = 221 ([M + ], 2); 105 

(100); 100 (5); 77 (16); 72 (5); 58 (7); 51 (6); 44 (8). HRMS 


½aŠ 23 

D ¼ 146:1 (c 0.5, CH2Cl2/MeOH, 96% ee (S)). Conversions 

were determined by GC (Agilent Technologies, 30 m,


50–300 °C, (50-8-260/5-8-280/5-8-300/5)) and ees by HPLC 

(Whelk (R,R), (S)-8a 8.29 min and (R)-8a 28.7 min (eluent: 

n-hexane/ethanol 99:1; flow: 1.0 ml/min)). 

4.4.2. (S)-1-Phenylethyl N,N-diethylcarbamate 8a. To a 

solution of (S)-1-phenylethanol (3.3 mmol) in THF 

(10 ml) was added NaH (3.4 mmol). The solution was stirred 

for 30 min at room temperature under an argon atmosphere. 

The solution was cooled to 0 °C and N,N-diethyl 

carbamoyl chloride (3.4 mmol) in THF (5 ml) was added. 

After stirring for 2 h at room temperature the reaction 

was quenched with water. The mixture was extracted with 

ethylacetate/n-hexane (1:1), washed with brine and dried 

over Na 2SO 4. The solvents were removed in vacuum and 

the crude oil was purified by flash column chromatography 

(ethylacetate/n-hexane 1:1) to yield a colourless oil (yield: 

56%). The analytical data are in agreement with 8a 

obtained by the hydrogenation protocol. 

4.4.3. 1-Phenylethyl N,N-dimethylcarbamate 9a. Oil. 1 H 

NMR (400 MHz, CDCl3) d = 7.34–7.22 (m, 5H, Ph); 5.78 

(q, 1H, J = 6.6 Hz, CH); 2.93 (br s, 3H, CH3); 2.88 (br s, 

3H, CH3); 1.51 (d, 3H, J = 6.6 Hz, CH3). 13 C NMR 

(100.6 MHz, CDCl 3) d = 156.0; 142.7; 128.5; 127.6; 125.9; 

73.1; 36.4; 35.9; 22.9. IR (KBr, cm 1 ): 3033 w; 2980 w; 

2932 w; 1704 s; 1495 m; 1450 m; 1393 m; 1273 w; 1191 s; 

1069 m; 1030 w; 1007 w; 995 w; 894 w; 844 w; 766 m; 

700 m; 638 w; 569 w; 532 w. MS (ESI): m/z (%) = 193 

([M + ], 6); 134 (13); 121 (1); 105 (100); 90 (1); 77 (13); 63 

(1); 51 (4). HRMS calcd for C 11H 15O 2N: 193.10973, found: 

193.109345. ½aŠ 22 

D ¼ 2:9 (c 0.3, CHCl3, 75% ee (S)). Conversions 

were determined by NMR and ees by HPLC 

(Chiralpak AD-H, (R)-9a 23.6 min and (S)-9a 31.3 min, 

eluent: n-hexane/ethanol 99:1; flow: 1.0 ml/min). The absolute 

configuration was assigned by analogy. 

4.4.4. 1-Phenylethyl N-methyl N-phenylcarbamate 10a. 

Oil. 1 H NMR (300 MHz, CDCl3) d = 7.35–7.16 (m, 10H, 

Ph); 5.83 (q, 1H, J = 6.5 Hz, CH); 3.28 (s, 3H, CH3); 

1.47 (d, 3H, J = 6.5 Hz, CHCH 3). 13 C NMR (75.5 MHz, 

CDCl3) d = 155.0; 143.4; 142.3; 128.8; 128.4; 127.6; 125.9 

(br); 125.8; 125.7 (br); 73.8; 37.7; 23.0. IR (KBr, cm 1 ): 

3064 w; 3033 w; 3980 m; 2932 w; 1706 s; 1598 m; 1496 s; 

1453 m; 1437 m; 1422 m; 1374 s; 1327 m; 1299 s; 1277 s; 

1210 m; 1159 s; 1113 m; 1063 s; 1029 m; 1010 m; 997 m; 

974 m; 912 w; 885 w; 819 w; 762 s; 698 s; 665 w; 625 w; 

599 w; 544 m. MS (ESI): m/z (%) = 255 ([M + ], 1); 211 

(2); 196 (7); 151 (1); 134 (2); 105 (100); 91 (1); 77 (20); 65 

(2); 51 (7). HRMS calcd for C16H17NO2: 255.12538, found: 

255.125229. ½aŠ 22 

D ¼þ19:9 (c 0.26, CHCl 3, 65% ee (S)). 

Conversions were determined by NMR and ees by HPLC 

(Chiralcel OD-H, (R)-10a 25.4 min and (S)-10a 47.2 min, 

eluent: n-hexane/ethanol 99:1; flow: 1.0 ml/min). The absolute 

configuration was assigned by analogy. 

4.4.5. 1-Phenylethyl N,N-diphenylcarbamate 11a. Crys- 

1 

tals. Mp: 76–78 °C. H NMR (300 MHz, CDCl3) 

d = 7.32–7.14 (m, 15H, Ph), 5.88 (q, 1H, J = 6.5 Hz, 

13 

CH), 1.47 (d, 3H, J = 6.5 Hz, CH3). C NMR 

(75.5 MHz, CDCl3) d = 154.1; 142.6; 141.9; 128.9; 128.4; 

127.7; 127.0; 126.1; 125.9; 74.3; 22.9. IR (KBr, cm 1 ): 

3064 w; 3033 m; 2984 m; 2934 w; 1702 s; 1591 s; 1491 s; 

1450 m; 1369 s; 1343 s; 1325 s; 1299 s; 1281 s; 1220 s; 

1208 s; 1178 m; 1159 w; 1128 w; 1058 s; 1048 s; 1023 s; 

1008 m; 993 m; 951 w; 913 w; 901 w; 860 m; 837 w; 814 

w; 781 m; 764 s; 758 s; 693 s; 672 m; 642 w; 622 w; 603 

w; 548 s; 516 m; 492 w. MS (ESI): m/z (%) = 317 ([M + ], 

2); 273 (2); 258 (2); 196 (1); 169 (41); 139 (1); 105 (100); 

77 (12); 51 (5). HRMS calcd for C21H19O2N: 317.14103, 

found: 317.141098. ½aŠ 21 

D ¼ 16:8 (c 0.33, CHCl 3,76%ee 

(R)). Conversions were determined by NMR and ees by 

HPLC (Chiralcel OD-H, (R)-11a 6.8 min and (S)-11a 

9.6 min, eluent: n-hexane/ethanol 99.5:0.5; flow: 1.0 ml/ 

min). The absolute configuration was assigned by analogy. 

4.4.6. 1-Phenylpropyl N,N-diethylcarbamate 12a. Colour- 

1 

less oil. Yield: 98%. H NMR (400 MHz, CDCl3) 

d = 7.28–7.16 (m, 5H, Ph); 5.54 (1H, dd, J = 6.4 Hz, 

J = 7.2 Hz, CHCH2); 3.23 (br, 4H, NCH2); 1.83 (m, 2H, 

CHCH2CH3); 1.06 (br, 6H, NCH2CH3); 0.83 (t, 3H, 

J = 7.4 Hz, CHCH2CH3). 13 C NMR (100.6 MHz, CDCl3) 

d = 155.5; 141.6; 128.3; 127.5; 126.4; 77.8; 41.8; 41.3; 

29.9; 14.3; 13.6; 9.9. IR (KBr, cm 1 ): 2972 m; 2934 m; 

2877 w; 1700 s; 1475 m; 1457 m; 1424 m; 1380 w; 1273 s; 

1226 w; 1171 s; 1063 m; 987 m; 903 w; 763 w; 700 m; 528 

w. MS (ESI): m/z (%) = 235 ([M + ], 9); 162 (15); 119 (54); 

100 (12); 91 (100); 77 (7). HRMS calcd for C14H19O2N: 

235.15668, found: 235.157242. ½aŠ 23 

D ¼ 143:7 (c0.5, CH2Cl2/MeOH, 50% ee). Conversions and ees were determined 

by GC (Retention time: 17.9 min, 30 m HP Agilent 

Technologies 50–300 °C: 50-8-260/5-8-280/5-8-300/5) and 

HPLC (Whelk (R,R), n-hexane/ethanol 98:2, flow 1.0 ml/ 

min, (S)-12a 4.84 min and (R)-12a 10.10 min). 

4.4.7. 3,3-Dimethylbutan-2-yl N,N-diethylcarbamate 14a. 

1 

Oil. H NMR (300 MHz, CDCl3) d = 4.56 (q, 1H, 

J = 6.4 Hz, CH); 3.25 (br d, 4H, CH2); 1.12 (d, 3H, 

J = 6.4 Hz, CH3); 1.10 (t, 6H, CH2CH3); 0.90 (s, 9H, 

CH3). 13 C NMR (75.5 MHz, CDCl3) d = 155.9; 78.1; 

41.6; 34.4; 25.9; 15.3; 14.2. IR (KBr, cm 1 ): 2971 s; 2935 

m; 2874 w; 1696 s; 1653 w; 1559 w; 1540 w; 1506 w; 1475 

m; 1457 m; 1423 s; 1395 w; 1378 m; 1365 w; 1316 w; 

1275 m; 1227 w; 1210 w; 1174 m; 1076 m; 1007 w; 972 w; 

893 w; 824 w; 783 w; 768 w; 744 w; 697 w; 617 w; 537 w. 

MS (ESI): m/z (%) = 201 ([M + ], 7); 186 (3); 144 (2); 116 

(16); 100 (100); 85 (44); 72 (25); 58 (21); 43 (46). HRMS 


½aŠ 22 

D ¼þ135 (c 0.04, CHCl3/MeOH, 67% ee). Conversions 

and ees were determined by GC (50m Chiraldex b-PH, 50.0 

m · 250 lm · 0.25 lm, 100/25-4-180/5, ( )-14a 25.6 min 

and (+)-14a 26.0 min). 

4.5. X-ray crystallographic studies of 5a, 5b and 6 

Data were collected with a STOE-IPDS diffractometer 

using graphite-monochromated Mo Ka radiation. The 

structures were solved by direct methods 19 and refined by 

full-matrix least-squares techniques against F 2 . 20 XP 

(BRUKER AXS) was used for graphical representations. 

The crystallographic data have been deposited with the 

Cambridge Crystallographic Data Centre as supplementary 

publication no. CCDC 641493–641495. Copies of the 

data can be obtained free of charge on application to 

http://www.ccdc.cam.ac.uk/data_request/cif.

4.5.1. Compound 5a. Space group P3 121, trigonal, a = 

11.174(2), c = 32.520(7) A ˚ , V = 3516(1) A ˚ 3 , Z =6, 

qcalcd = 1.230 g cm 3 , 18,941 reflections measured, 3621 

were independent of symmetry, of which 2550 were observed 

(I >2r(I)), R1 = 0.055, wR 2 (all data) = 0.145, 281 

parameters, Flack parameter x = 0.05(18). 

4.5.2. Compound 5b. Space group P2 1, monoclinic, a = 

7.985(2), b = 11.407(2), c = 12.625(3) A ˚ , b = 98.27(3)°, 

V = 1138.0(4) A ˚ 3 , Z =2, qcalcd = 1.262 g cm 3 , 15,617 

reflections measured, 4452 were independent of symmetry, 

of which 2645 were observed (I >2r(I)), R1 = 0.034, wR 2 

(all data) = 0.059, 289 parameters, Flack parameter 

x = 0.02(8). 

4.5.3. Compound 6. Space group P21, monoclinic, a = 

9.445(2), b = 16.801(3), c = 14.081(3) A ˚ , b = 91.75(3)°, 

V = 2233.4(8) A ˚ 3 , Z =4, qcalcd = 1.292 g cm 3 , 13,676 

reflections measured, 7244 were independent of symmetry, 

of which 5881 were observed (I >2r(I)), R1 = 0.047, wR 2 

(all data) = 0.118, 577 parameters, Flack parameter x = 

0.07(10). 

Acknowledgements 

We thank Mrs. M. Heyken, Mrs. S. Buchholz and Dr. C. 

Fischer (all Leibniz-Institut für Katalyse e.V. an der Universität 

Rostock) for excellent technical and analytical 

assistance. Dr. B. Hagemann is gratefully thanked for the 

synthesis of ligand 4e. Generous financial support from 

the state of Mecklenburg-Western Pomerania and the 

BMBF as well as the Deutsche Forschungsgemeinschaft 

(Leibniz-price) are gratefully acknowledged. 

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17. The reaction is stopped after 1 h and a black precipitate 

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6. Transfer hydrogenation 

6.1. Homogeneous iron catalyst in reduction chemistry 

6.1.1. An environmentally benign process for the hydrogenation of ketones 

with homogeneous iron catalysts 

Stephan Enthaler, Bernhard Hagemann, Giulia Erre, Kathrin Junge, and Matthias Beller*, 

Chem. Asian. J. 2006, 1, 598–604. 

Contributions 

The BuP(Ad)2 ligand was synthesized by Dr. R. Jackstell. 

100

FULL PAPERS 

DOI: 10.1002/asia.200600105 

An Environmentally Benign Process for the Hydrogenation of Ketones with 

Homogeneous Iron Catalysts 

Stephan Enthaler, Bernhard Hagemann, Giulia Erre, Kathrin Junge, and 

Matthias Beller* [a] 

Abstract: Iron complexes generated 

in situ catalyze homogeneously the 

transfer hydrogenation of aliphatic and 

aromatic ketones by utilizing 2-propanol 

as a hydrogen donor in the presence 

of base. The influence of different 

reaction parameters on the catalytic activity 

is investigated in detail by apply- 

Introduction 

Catalysis is a key technology for the advancement of green 

chemistry, specifically for waste prevention, decreasing 

energy consumption, achieving high atom efficiency and 

generating advantageous economics. [1] There is an increasing 

interest in substituting toxic and expensive late transition 

metals by readily available and less-toxic metals. In this 

regard, the use of iron catalysts is especially desirable. [2] So 

far, homogeneous iron catalysts have been successfully applied 

for various C C coupling reactions such as Friedel– 

Crafts-type reactions, olefin polymerizations, cross-couplings, 

cycloadditions, and substitution reactions. [3] However, 

much less is known in the area of industrially important catalytic 

reductions. Here, comparatively few Fe-catalyzed hydrogenations 

have been established, mainly for the reduction 

of olefins [4] and nitro compounds. [5] Clearly, the quest 

for practical hydrogenation catalysts based on Fe complexes 

constitutes a major challenge for the development of more 

sustainable reductions. 

Recently, we became interested in applying homogeneous 

Fe catalysts with respect to C H functionalization reactions 

[a] S. Enthaler, B. Hagemann, G. Erre, Dr. K. Junge, Prof. Dr. M. Beller 

Leibniz-Institut für Katalyse e.V. an der Universität Rostock 

Albert-Einstein-Str. 29a 

18059 Rostock (Germany) 

Fax: (+ 49) 381-1281-5000 

E-mail: matthias.beller@ifok-rostock.de 

ing a three-component catalyst system 

composed of an iron salt, 2,2’:6’,2’’-terpyridine, 

and PPh 3. The scope and limi- 

Keywords: homogeneous catalysis · 

iron · ketones · ligand effects · 

transfer hydrogenation 

tations of the described catalyst is 

shown in the reduction of 11 different 

ketones. In most cases, high conversion 

and excellent chemoselectivity are obtained. 

Mechanistic studies indicate a 

monohydride reaction pathway for the 

homogeneous iron catalyst. 

of arenes. [6] Based on that work and our ongoing research in 

hydrogenation chemistry, [7] we started to explore Fe catalysts 

for transfer hydrogenations [8] of carbonyl compounds. 

To the best of our knowledge, only iron carbonyls [9,10] or 

complexes that contain tetradentate aminophosphines [11] or 

phosphines [12] have been described for the transfer hydrogenations 

of ketones and a,b-unsaturated carbonyl compounds. 

In the latter case, mainly hydrogenation of the 

olefin occurred. [9,12] 

Our goal is to develop a practical Fe hydrogenation catalyst 

system, which should be easy to prepare and tunable. 

Thus, the use of commercially available Fe complexes in 

combination with two different ligands (phosphines and 

amines) instead of tetradentate ligands seems to be a useful 

approach. Based on this idea, we report herein the application 

of new three-component iron catalysts prepared in situ 

based on iron salts, 2,2’:6’,2’’-terpyridine (terpy), and PPh 3. 

These catalysts give excellent yield and selectivity in the reduction 

of aromatic and aliphatic ketones to alcohols. 

Results and Discussion 

As a starting point, 2-propanol-based transfer hydrogenation 

of acetophenone (1) was examined with Fe catalysts in the 

presence of combinations of nitrogen and phosphorus ligands. 

In exploratory experiments, terpy and PPh 3 were 

used as ligands. Typically, the precatalyst was prepared 

in situ by stirring a solution of [Fe 3(CO) 12] (0.3 mol %), 

terpy (1 mol %), and PPh 3 (1 mol %) in 2-propanol (1.0 mL) 

598 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Asian J. 2006, 1, 598 – 604

for 16 h at 65 8C. Initially, we investigated the influence of 

terpy and PPh 3 in the presence of [Fe 3(CO) 12], which can be 

easily handled without special precautions (Table 1). To our 

Table 1. Transfer hydrogenation of acetophenone (1) with 

ACHTUNGTRENUNG[Fe 3(CO) 12]/terpy/PPh 3 catalyst. [a] 

Entry Terpy [b] 

PPh 3 [b] 

Yield [%] [c] 

Selectivity [%] [d] 

1 – – 23 > 99 

2 1 1 78 > 99 

3 1 – 18 > 99 

4 – 1 6 > 99 

5 – 2 21 > 99 

6 – 10 29 > 99 

7 5 1 27 > 99 

8 1 5 24 > 99 

[a] Reaction conditions: in situ catalyst (0.0038 mmol) ([Fe3(CO) 12] 

(0.0013 mmol), terpy (0.0038 mmol), PPh3 (0.0038 mmol), 2-propanol 

(2.0 mL) for 16 h at 658C), iPrONa (0.019 mmol), 5 min at 100 8C, then 

addition of 1 (0.38 mmol), 7 h at 100 8C. [b] Ligand to Fe ratio. [c] Yield 

was determined by GC (50 m Lipodex E, 95–200 8C) with diglyme as internal 

standard (yield is equivalent to conversion). [d] Selectivity refers 

to chemoselectivity. 

delight, a 1:1 mixture of terpy and PPh 3 gave an active catalyst 

for the test reaction that was superior to all other combinations 

(Table 1, entry 2). Notably, low catalytic activity 

was observed without the use of any ligands (Table 1, 

entry 1). Increasing the ligand concentration resulted in a 

significant decrease in activity (Table 1, entries 7 and 8). Importantly, 

the catalyst systems differ mainly with respect to 

reactivity, as the chemoselectivity was excellent in all cases. 

Next, the influence of base and the iron precatalyst was 

investigated in more detail (Table 2). The best results were 

obtained with [Fe 2(CO) 9] and [Fe 3(CO) 12] in the presence of 

catalytic amounts of sodium 2-propylate or sodium tert-bu- 

ACHTUNGTRENUNGtylate (Table 2, entries 1, 6, 16). Surprisingly, the most commonly 

used bases for transfer hydrogenation, such as 

NaOH, KOH, and tBuOK, showed only low activity in this 

model reaction (Table 2, entries 3–5). Furthermore, different 

inorganic bases such as K 2CO 3, Cs 2CO 3, and K 3PO 4 

(Table 2, entries 7–9) as well as nitrogen-containing organic 

bases, for instance, pyridine, NEt 3, NACHTUNGTRENUNG(iPr) 2Et, DBU, and 

DABCO (Table 2, entries 10–14), did not prove to be effective. 

As expected, no transfer of hydrogen was observed in 

the absence of base (Table 2, entry 15). 

To improve the catalytic system, various iron sources with 

different oxidation states (0, +2, and +3) were tested. Besides 

[Fe 2(CO) 9] and [Fe 3(CO) 12], FeCl 2 (Table 2, entry 20) 

also produced reasonable conversion. To facilitate the formation 

of active iron hydride complexes, we tested [Et 3NH]- 

ACHTUNGTRENUNG[HFe(CO) 4] [13] as precatalyst, but only limited conversion 

was detected (Table 2, entry 19). 

Following these results, we focused on the nature of the ligands. 

The results in Table 3 indicate no improvement of 

Table 2. Influence of different bases and iron sources in the Fe-catalyzed 

transfer hydrogenation of 1. [a] 

Entry Iron source Base Yield [%] [b] 

1 ACHTUNGTRENUNG[Fe3(CO) 12] iPrONa 78 

2 ACHTUNGTRENUNG[Fe3(CO) 12] LiOH 2 

3 ACHTUNGTRENUNG[Fe3(CO) 12] NaOH < 1 

4 ACHTUNGTRENUNG[Fe3(CO) 12] KOH < 1 

5 ACHTUNGTRENUNG[Fe3(CO) 12] tBuOK 12 

6 ACHTUNGTRENUNG[Fe3(CO) 12] tBuONa 76 

7 ACHTUNGTRENUNG[Fe3(CO) 12] K2CO3 3 

8 ACHTUNGTRENUNG[Fe3(CO) 12] Cs2CO3 3 

9 ACHTUNGTRENUNG[Fe3(CO) 12] K3PO4 < 1 

10 ACHTUNGTRENUNG[Fe3(CO) 12] pyridine 1 

11 ACHTUNGTRENUNG[Fe3(CO) 12] NEt3 2 

12 ACHTUNGTRENUNG[Fe3(CO) 12] NACHTUNGTRENUNG(iPr) 2Et < 1 

13 ACHTUNGTRENUNG[Fe3(CO) 12] DBU < 1 

14 ACHTUNGTRENUNG[Fe3(CO) 12] DABCO < 1 

15 ACHTUNGTRENUNG[Fe3(CO) 12] – 0 

16 ACHTUNGTRENUNG[Fe2(CO) 9] iPrONa 84 

17 [Fe(CO) 5] iPrONa 2 

18 ACHTUNGTRENUNG[CpFe(CO) 2I] iPrONa 3 

19 ACHTUNGTRENUNG[Et3NH]ACHTUNGTRENUNG[HFe(CO) 4] iPrONa 11 

20 FeCl2 iPrONa 45 

21 FeCl3·xH2O iPrONa < 1 

22 FeBr2 iPrONa 9 

23 FeSO4·7H2O iPrONa 9 

24 FeACHTUNGTRENUNG(acac) 2 iPrONa 17 

25 FeACHTUNGTRENUNG(acac) 3 iPrONa 3 


(0.0013 mmol), terpy (0.0038 mmol), PPh3 (0.0038 mmol), 2-propanol 

(2.0 mL) for 16 h at 65 8C), base (0.019 mmol), 5 min at 100 8C, then addition 

of 1 (0.38 mmol), 7 h at 100 8C. [b] Yield was determined by GC 

(50 m Lipodex E, 95–200 8C) with diglyme as internal standard (yield is 

equivalent to conversion). acac = Acetylacetonate, Cp = cyclopentadienyl, 

DABCO=1,4-diazabicycloACHTUNGTRENUNG[2.2.2]octane, 

undec-7-ene. 

DBU= 1,8-diazabicycloACHTUNGTRENUNG[5.4.0]- 

conversion when PPh 3 was substituted by other phosphorus 

ligands. Variation in the substitution pattern of PPh 3 with 

electron-donating (Table 3, entry 2) or electron-withdrawing 

groups (Table 3, entries 3–5) as well as more-basic and sterically 

hindered phosphines (Table 3, entries 6–9) decreased 

the yield of 1-phenylethanol (2). We also applied diphosphine 

ligands in the model reaction. Good activity was obtained 

with 1,1-bis-(diphenylphosphanyl)methane (dppm) 

and 1,2-bis(diphenylphosphanyl)ethane (dppe) (Table 3, entries 

12–13). Next, we explored the nature of the nitrogencontaining 

ligand. To our surprise, substituted terpyridines 

such as 4’-chloro-2,2’:6’,2’’-terpyridine (3), 6,6’-dibromo- 

2,2’:6,6’-terpyridine (4), and 4,4’,4’’-tri-tert-butyl-2,2’:6,2’’-terpyridine 

(5) led to a significant decrease in alcohol formation 

(Table 4, entries 1–4). Similarly, the application of structurally 

related N,N’,N’’-ligands 6 and 7 showed no pronounced 

activity (Table 4, entries 5 and 6). However, in the 

presence of pyridine (3 mol %) and triACHTUNGTRENUNGphenylphosphine, a 

reasonable yield of 2 (54%) was obtained. Clearly, Fe/pyridine/PPh 

3 represents one of the least demanding homogenous 

transfer-hydrogenation catalysts around. Furthermore, 

Chem. Asian J. 2006, 1, 598 – 604 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemasianj.org 599

FULL PAPERS 

Table 3. Influence of phosphorus ligands in the Fe-catalyzed transfer 

ACHTUNGTRENUNGhydrogenation of 1. [a] 

Entry Phosphine Conversion [%] [b] 

1 PPh 3 78 

2 P(p-MeO-C 6H 4) 3 13 

3 P(p-Me-C 6H 4) 3 22 

4 PACHTUNGTRENUNG(p-F-C 6H 4) 3 23 

5 P(3,4-CF 3-C 6H 3) 3 5 

6 PCy 3 11 

7 PACHTUNGTRENUNG(tBu) 3 32 

8 34 

9 31 

10 PACHTUNGTRENUNG(OPh) 3 8 

11 PACHTUNGTRENUNG(OiPr) 3 7 

12 Ph2PCH2PPh2 64 

13 Ph2PACHTUNGTRENUNG(CH2) 2PPh2 50 




(0.0013 mmol), terpy (0.0038 mmol), phosphorus ligand (0.0038 mmol), 2propanol 

(2.0 mL) for 16 h at 658C), iPrONa (0.019 mmol), 5 min at 

100 8C, then addition of 1 (0.38 mmol), 7 h at 100 8C. [b] Yield was determined 

by GC (50 m Lipodex E, 95–200 8C) with diglyme as internal standard 

(yield is equivalent to conversion). Cy = cyclohexyl. 

the combination of ( )-sparteine and triphenylphosphine 

provided an active catalyst system (Table 4, entries 11–12). 

Next, the optimized general protocol for transfer hydrogenations 

was applied to aromatic and aliphatic ketones. Here, 

both [Fe 3(CO) 12]/terpy/PPh 3 and FeCl 2/terpy/PPh 3 were 

tested for the reduction of 10 different ketones (Table 5). 

Acetophenone, 4-chloroacetophenone, 2-methoxyaceto- 

ACHTUNGTRENUNGphenone, and propiophenone were hydrogenated in excellent 

yield and selectivity (92–99 %) (Table 5, entries 1, 2, 5, 

6). Acetophenones with electron-donating substituents in 

the para position gave good but somewhat lower yields (75– 

83 %). A chloro substituent in the a position to the carbonyl 

group proved to be problematic and deactivated both catalysts 

(Table 5, entry 7). Aliphatic ketones are more challenging 

substrates than aromatic ketones, but they also react in 

excellent yield (95–99 %). 

Notably, similar activities for the reduction of ketones 

with regard to our [Fe 3(CO) 12]-based system were reported 

when other transition-metal carbonyl complexes, for instance, 

[Ru 3(CO) 12]-based catalysts, were applied. [14] The 

[Fe 3(CO) 12]- and FeCl 2-based catalysts showed no significant 

difference in productivity. Hence, we assume the formation 

of a similar active species. Indeed, the two catalyst systems 

produced similar conversion curves (Figure 1). At the start 

of the reaction, we observe in both cases an induction 

M. Beller et al. 

Figure 1. Conversion–time behavior of the different precatalysts containing 

[Fe 3(CO) 12] and FeCl 2. Reaction conditions: in situ catalyst 

(0.0038 mmol) ([Fe 3(CO) 12] (0.0013 mmol) or FeCl 2 (0.0038 mmol), terpy 

(0.0038 mmol), and PPh 3 (0.0038 mmol) in 2-propanol (2.0 mL), 16 h at 

658C), iPrONa (0.38 mmol), 5 min at 100 8C, then addition of 1 

(0.76 mmol), reaction at 100 8C. Conversion was determined by GC (50 m 

Lipodex E, 95-200 8C) with diglyme as internal standard (conversion is 

equivalent to yield). ^=[Fe 3(CO) 12]/terpy/PPh 3, & = FeCl 2/terpy/PPh 3. 

period of nearly one hour, whereby the FeCl 2 system 

showed a slightly lower reaction rate, probably due to the 

slower elimination of chlorides and the change of oxidation 

state. The induction period can be shortened by increasing 

the catalyst preformation time. Thus, when the precatalyst 

([Fe 3(CO) 12]/terpy/PPh 3) was treated with a base for one 

hour instead of 5 min at the reaction temperature, an increase 

in conversion into 1-phenylACHTUNGTRENUNGethanol from 18 % to 

32 % in the first hour was recorded. 

Next, we focused our attention on the reaction mechanism. 

To exclude the formation of heterogeneous Fe catalysts, 

[15] a large excess of Hg(0) was added to the well-stirred 

reaction mixture after the reaction had proceeded for one 

hour, so that the “real” catalyst should be formed. [16, 17] No 

significant suppression of the reaction rate in the reduction 

of 1 was observed (73 % yield after 7 h), whereas a positive 

poisoning of the catalyst should have led to approximately 

18 % of 2 (see also Figure 1). In another experiment, the reaction 

was carried out under standard conditions and filtered 

through celite after one hour. [18] The filtrate was allowed 

to react for a further six hours. Thereafter, the applied 

celite was stirred with fresh 2-propanol, sodium 2-propylate, 

and 1 under reaction conditions for another six 

hours. The results obtained showed no suppression of reaction 

rate for the filtrate (92 %), whereas no conversion was 

detected (< 1 %) with the celite system. Consequently, both 

experiments indicate a definite homogeneous catalyst. 

Various methods ( 1 H, 31 P, and 13 C NMR and IR spectroscopy 

and MS) were used for the characterization of the 

active catalyst species. Unfortunately, the structural composition 

of the catalyst is still unclear. No evidence for an Fe 

H species was detected by 1 H NMR spectroscopy after reaction 

of the precatalyst with base (5 equiv). [19] The 31 P NMR 

spectrum of the precatalyst in [D 4]MeOH or [D 8]iPrOH 

showed three singlets with a ratio of 20:1:10 at 5.3 ppm 

600 www.chemasianj.org 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Asian J. 2006, 1, 598 – 604

Ketone Hydrogenation with Homogeneous Iron Catalysts 

Table 4. Variation of nitrogen ligands in the Fe-catalyzed transfer 

ACHTUNGTRENUNGhydrogenation of 1. [a] 

Entry Ligand Ligand/metal Conversion [%] [b] 

1 terpy 1 78 

2 3 1 23 

3 4 1 28 

4 5 1 14 

5 6 1 13 

6 7 1 7 

7 2,2’-bipyridine 1 8 

8 2,2’-bipyridine 2 6 

9 tmeda [c] 

1 18 

10 tmeda [c] 

2 13 

11 ( )-sparteine 1 43 [d] 

12 ( )-sparteine 2 38 [d] 

13 pyridine 3 54 

14 pyridine 6 5 


(0.0013 mmol), nitrogen ligand (0.0038 mmol), PPh3 (0.0038 mmol), 2propanol 

(2.0 mL) for 16 h at 658C), iPrONa (0.019 mmol), 5 min at 

100 8C, then addition of 1 (0.38 mmol), 7 h at 100 8C. [b] Yield was determined 

by GC (50 m Lipodex E, 95–200 8C) with diglyme as internal standard 

(yield is equivalent to conversion). [c] tmeda = N,N,N’,N’-tetrameth- 

ACHTUNGTRENUNGylethylendiamine. [d] A racemic mixture of 2 was detected. 

(free PPh 3) and two unknown signals at 32.9 and 

71.3 ppm. [20] The addition of 5 equivalents of base (sodium 

2-propylate) with respect to iron and stirring of the mixture 

for 5 min at 100 8C did not affect the chemical shift and 

ratio of the observed 31 P NMR signals. [19] Mass spectrometric 

investigations also gave no clear information about the composition 

of the precatalyst, because indications for a number 

of possible candidates or fragments of labile complexes 

were detected, such as compounds containing terpy, PPh 3, 

CO, and Fe in a ratio of 1:1:1(2):1 or terpy, CO, and Fe in a 

ratio of 1:3:1. The utilization of [Fe 3(CO) 12] represents a potential 

option for IR spectroscopy. Hence, we recorded the 

IR spectra of our precatalyst in a solution of 2-propanol. 

The activation of the precatalyst by sodium 2-propylate 

(10 equiv) for 5 min at 100 8C resulted in the http:// 

www.dict.cc/?s =disappearance of absorption signals at 1889 

and 1718 cm 1 . Addition of 1 to the activated precatalyst led 

to the http://www.dict.cc/?s =disappearance of the signal at 

1654 cm 1 and emergence of a signal at 1679 cm 1 . Interestingly, 

a similar behavior was described by Gao and co-workers 

when they followed the formation of the transfer-hydrogenation 

catalyst composed of [Fe 3(CO) 12] and tetradentate 

aminophosphines in 2-propanol in the presence of base. [11] 

Although the nature of the active Fe H species remains 

unclear, we turned our attention to the mechanism of the 

hydride transfer. To exclude a radical-type reduction, the reaction 

of cyclopropyl phenyl ketone was examined in more 

detail (“radical clock” substrate) (Table 5, entry 8). In the 

presence of [Fe 3(CO) 12]/terpy/PPh 3 catalyst, the corresponding 

cyclopropyl phenyl alcohol 14 was detected by 1 H NMR 

spectroscopy in >99 % purity. There was apparently no radical-induced 

reduction, because no opening of the cyclopro- 

ACHTUNGTRENUNGpyl ring occurred. [21] Consequently, a radical-reduction 

mechanism promoted by sodium alkoxides, whereby the 

transition metal plays a marginal role, can also be excluded. 

[22] 

In general, for transition-metal-catalyzed transfer hydrogenation, 

two mechanisms are accepted: direct hydrogen 

transfer via formation of a six-membered cyclic transition 

state composed of metal and hydrogen donor and acceptor, 

and the hydridic route, which is subdivided into two pathways, 

the monohydride and the dihydride mechanism 

(Scheme 1). More specifically, the formation of monohydride 

metal complexes promote an exclusive hydride transfer 

from carbon (donor) to carbonyl carbon (acceptor) 

(Scheme 1, pathway A), whereas a hydride transfer from 

carbon (donor) to carbonyl carbon (acceptor) as well as carbonyl 

oxygen (acceptor) was proposed for the formation of 

dihydride metal complexes (Scheme 1, pathway B). [8a,c,e] Evidence 

for both pathways (hydridic route) were determined 

by various researchers when investigating the hydride transfer 

catalyzed by metal complexes of, for example, Ru, Rh, 

or Ir. [23] So far nothing is known with respect to iron catalysts 

in transfer hydrogenations. 

To rule out an exchange of hydrogen atoms, for example, 

by C H activation, we investigated the transfer hydrogenation 

with a completely deuterated donor molecule. [24] The 

[Fe 3(CO) 12]/terpy/PPh 3 precatalytic system was dissolved in 

[D 8]iPrOH and treated with [D 7]iPrONa for 5 min at 100 8C. 

After addition of 1, the solution was stirred for 5 h at 

100 8C. Only alcohol 17 was detected as product by 1 H NMR 

spectroscopy (Scheme 2; >99 %). [25] This result indicates an 

exclusive transfer of the deuterium into the carbonyl group. 

Apparently no C H activation processes and enol formation 

occurred under the described conditions. [26] 

To clarify the pathway of hydrogen transfer from the hydrogen 

donor to the substrate molecule, we used [D]iPrOH 

(the hydroxy group was deuterated) as solvent/donor and 

sodium 2-propylate as base in the transfer hydrogenation of 

1 (Scheme 2). We obtained a mixture of two different deuterated 

1-phenylethanols 18 and 19 in the ratio 85:15. [27] 


FULL PAPERS 

Table 5. ACHTUNGTRENUNG[Fe 3(CO) 12]/terpy/PPh 3- and FeCl 2/terpy/PPh 3-catalyzed 

ACHTUNGTRENUNGhydrogenation of ketones. [a] 

Entry Alcohol Yield [%] [b] 

ACHTUNGTRENUNG[Fe 3(CO) 12] 

1 95 91 

2 > 99 97 

3 84 83 

4 63 75 

5 > 99 > 99 

6 81 92 

7 5 8 

8 48 57 

9 95 93 

10 > 99 > 99 

Yield [%] [b] 

FeCl 2 

[a] Reaction conditions: in situ catalyst (0.0038 mmol) ([Fe 3(CO) 12] 

(0.0013 mmol) or FeCl 2 (0.0038 mmol), terpy (0.0038 mmol), PPh 3 

(0.0038 mmol) in 2-propanol (2.0 mL), 16 h at 658C), iPrONa 

(0.38 mmol), 5 min at 100 8C, then addition of ketone (0.76 mmol), reaction 

for 7 h at 100 8C. [b] Yield was determined by GC (2: 50 m Lipodex 

E, 95–200 8C, 8: 25 m Lipodex E, 100 8C, 9: 50 m Lipodex E, 90–105 8C, 

10: 25 m Lipodex E, 80–180 8C, 11, 14, 15, and 16: 30 m, HP Agilent 

Technologies, 50–300 8C, 12: 25 m Lipodex E, 90–180 8C, 13: 50 m Lipodex 

E, 90–180 8C) with diglyme as internal standard (yield is equivalent 

to conversion). 

This specific migration is in agreement with the described 

monohydride mechanism, which implies that a major formation 

of the metal monohydride in the catalytic cycle occurred, 

albeit with a small amount of 19. [8c] This H/D scrambling 

is explained by the reversibility of the hydrogen-transfer 

process due to the hydrogen-donating ability of 

1-phenylethanol (low oxidation potential). [8c] 

Scheme 1. Monohydride (pathway A) and dihydride (pathway B) mechanisms 

of transition-metal-catalyzed transfer hydrogenation of acetophenone. 

Scheme 2. Deuterium incorporation into acetophenone (1) catalyzed by 

[Fe 3(CO) 12]/terpy/PPh 3 in the presence of base. 

Conclusions 

We have developed the first general homogeneous Fe catalyst 

system for the transfer hydrogenation of aliphatic and 

aromatic ketones. In the presence of 1 mol % of [Fe 3(CO) 12]/ 

terpy/PPh 3 or FeCl 2/terpy/PPh 3, the corresponding alcohols 

are obtained in good to excellent yield and chemoselectivity. 

The active catalyst systems are easily generated in the presence 

of cheap available nitrogen and phosphorus ligands. 

Mechanistic experiments indicate a transfer of hydrogen 

from the donor molecule to the substrate by a monohydride 

mechanism. Further work in the direction of stereoselective 

Fe-based hydrogenation catalysts is under way in our laboratories. 

General 



All manipulations were performed under argon atmosphere with standard 

Schlenk techniques. Unless otherwise specified, all chemicals are 

commercially available and used as received. 2-Propanol, pyridine, and 

triethylamine were used without further purification (purchased from 

Fluka, dried over molecular sieves). Sodium 2-propylate and sodium tertbutylate 

were prepared by treating sodium with 2-propanol or tert-butanol 

under argon atmosphere (stock solution). Ketones 1, 8, 9, 11, 12, 14, 


Ketone Hydrogenation with Homogeneous Iron Catalysts 

15, and 16 were dried over CaH 2, distilled under vacuum, and stored 

under argon. Ketones 10 and 13 were treated with vacuum/argon cycles 

and stored under argon. Tmeda was distilled under Argon. [Et 3NH]- 

ACHTUNGTRENUNG[HFeCO 4], [13] BuP(adamantyl) 2, [28] and N-phenyl-2-(di-tert-butylphos- 

ACHTUNGTRENUNGphanyl)pyrrole [29] were synthesized according to literature protocols. 

[D 8]- and [D]iPrOH were dried over CaH 2 and distilled under argon atmosphere. 

General Procedure for Transfer Hydrogenation of Ketones 

In a Schlenk tube (10 mL), the catalyst (0.0038 mmol) was generated 

in situ by stirring a solution of [Fe 3(CO) 12] (0.0013 mmol), terpy 

(0.0038 mmol), and PPh 3 (0.0038 mmol) in 2-propanol (1.0 mL) for 16 h 

at 658C. The precatalytic system was treated with sodium 2-propylate 

(0.38 mmol) at 100 8C for 5 min. After addition of the corresponding 

ketone (0.38 or 0.76 mmol), the reaction mixture was stirred for 7 h at 

100 8C. The solution was cooled to room temperature and filtered over a 

plug of silica. The conversion was measured by GC without further purification. 

Procedures for Distinguishing Homogeneous and Heterogeneous Catalysts 

Mercury poisoning: In a Schlenk tube (10 mL), a solution of [Fe3(CO) 12] 

(0.0013 mmol), terpy (0.0038 mmol), and PPh3 (0.0038 mmol) in 2-propanol 

(1.0 mL) was stirred for 16 h at 658C. The precatalyst was treated at 

100 8C with sodium 2-propylate (0.38 mmol) in 2-propanol (0.5 mL) for 

5 min, followed by 1 (0.76 mmol) in 2-propanol (0.5 mL). The reaction 

mixture was kept for 1 h at 100 8C. After that, a drop of mercury, which 

was degassed and stored under argon, was added, and the reaction was 

continued for 7 h. The reaction mixture was cooled to room temperature 

and filtered over a plug of silica gel. The conversion was determined by 

GC without further purification. 

Maitlis test: In a Schlenk tube (10 mL), a solution of [Fe3(CO) 12] 

(0.0013 mmol), terpy (0.0038 mmol), and PPh3 (0.0038 mmol) in 2-propanol 

(1.0 mL) was stirred for 16 h at 658C. The precatalyst was treated at 

100 8C with sodium 2-propylate (0.38 mmol) in 2-propanol (0.5 mL) for 

5 min, followed by 1 (0.76 mmol) in 2-propanol (0.5 mL). The reaction 

mixture was kept for 1 h at 100 8C. After that, the solution was filtered 

under an atmosphere of argon through a filter supported by a plug of 

celite (heated in vacuum and stored under argon). The filtrate was 

heated again to 100 8C and the reaction allowed to proceed for another 

6 h. The celite phase was transferred into a Schlenk tube (10 mL) and 

mixed with 2-propanol (1.0 mL), sodium 2-propylate (0.38 mmol) in 2propanol 

(0.5 mL), and 1 (0.76 mmol) in 2-propanol (0.5 mL). After the 

reaction was complete, both mixtures were cooled to room temperature 

and filtered over a plug of silica gel. The conversion was determined by 

GC without further purification. 

Transfer Hydrogenation with [D 8]iPrOH as Hydride Source 

In a Schlenk tube (10 mL), [Fe 3(CO) 12] (0.0013 mmol), terpy 

(0.0038 mmol), and PPh 3 (0.0038 mmol) in [D 8]iPrOH (1.0 mL) were stirred 

for 16 h at 658C. After mixing the precatalytic solution with 

[D 7]iPrONa (0.38 mmol, prepared by reacting sodium (0.38 mmol) with 

[D 8]iPrOH (0.5 mL)) at 100 8C for 5 min, a solution of 1 (0.76 mmol) in 

[D 8]iPrOH (0.5 mL) was added. The reaction mixture was kept for 5 h at 

100 8C, then cooled to room temperature and filtered over a plug of 

silica. The conversion was determined by 1 H NMR spectroscopy. 

Transfer Hydrogenation with [D]iPrOH as Hydride Source 

In a Schlenk tube (10 mL), [Fe 3(CO) 12] (0.0013 mmol), terpy 

(0.0038 mmol), and PPh 3 (0.0038 mmol) in [D]iPrOH (1.0 mL) were stirred 

for 16 h at 658C. After mixing the precatalytic solution with sodium 

2-propylate (0.38 mmol, prepared by treating sodium (0.38 mmol) with 

[D]iPrOH (0.5 mL)) at 100 8C for 5 min, a solution of 1 (0.76 mmol) in 

[D]iPrOH (0.5 mL) was added. The reaction mixture was kept for 5 h at 

100 8C. (To avoid side effects, for instance, scrambling, the reaction was 

stopped before full conversion.) The solution was cooled to room temperature 

and filtered over a plug of silica. The solvent was removed under 

vacuum, and the residue was dissolved in CDCl 3. The conversion was de- 

termined by 1 H NMR spectroscopy. The ratio of 18 to 19 was based on 

the integrals of the 1 H NMR signals of the CH 3 groups. 


This work was financed by the State of Mecklenburg-Vorpommern and 

the Bundesministerium für Bildung und Forschung (BMBF). We thank 

Mrs. C. Voss, Mrs. C. Mewes, Mrs. M. Heyken, Mrs. S. Buchholz, and Dr. 

C. Fischer (all Leibniz-Institut für Katalyse e.V. an der Universität Rostock) 

for their excellent technical and analytical support. 

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[19] The preparation of the precatalyst was carried out in a similar 

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Chem. 2002, 114, 2108 – 2123; Angew. Chem. Int. Ed. 2002, 41, 2008 – 

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Kavana, J. Am. Chem. Soc. 2001, 123, 1090 –1100; p) O. Pàmies, 

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2829; v) A. Aranyos, G. Csjernyik, K. J. Szabó, J. E. Bäckvall, Chem. 

Commun. 1999, 351 –352; w) M. L. S. Almeida, M. Beller, G. Z. 

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[24] a) L. Dahlenburg, R. Gçtz, Eur. J. Inorg. Chem. 2004, 88 –905; 

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3358. 

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[27] The ratio of 18 to 19 was determined by 1 H NMR spectroscopy 

based on the integrals of the signals for the CH 3 groups. 

[28] A. Ehrentraut, A. Zapf, M. Beller, Synlett 2000, 1589 – 1592. 

[29] A. Zapf, R. Jackstell, F. Rataboul, T. Riermeier, A. Monsees, C. 

Fuhrmann, N. Shaikh, U. Dingerdissen, M. Beller, Chem. Commun. 

2004, 38 –39. 

Received: April 4, 2006 

Revised: July 5, 2006 




6.1.2. Biomimetic transfer hydrogenation of ketones with iron 

porphyrin catalysts 

Stephan Enthaler, Giulia Erre, Man Kin Tse, Kathrin Junge, and Matthias Beller*, 

Tetrahedron Lett. 2006, 47, 8095–8099. 

Contributions 

Ligands 1a and 1d were synthesized by Dr. M. K. Tse. 

108

Biomimetic transfer hydrogenation of ketones with iron 

porphyrin catalysts 

Stephan Enthaler, Giulia Erre, Man Kin Tse, Kathrin Junge and Matthias Beller * 

Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Str. 29a, D-18059 Rostock, Germany 

Received 17 July 2006; revised 11 September 2006; accepted 12 September 2006 

Available online 4 October 2006 

Abstract—For the first time in situ generated iron porphyrins have been applied as homogeneous catalysts for the transfer hydrogenation 

of ketones. Using 2-propanol as hydrogen source various ketones are reduced to the corresponding alcohols in good to 

excellent yield and selectivity. Under optimized reaction conditions high catalyst turnover frequencies up to 642 h 1 are achieved. 

Ó 2006 Elsevier Ltd. All rights reserved. 

Alcohols are key intermediates for the synthesis of pharmaceuticals, 

agrochemicals, polymers and new materials. 

1,2 Starting from carbonyl compounds various 

catalytic approaches toward the synthesis of alcohols 

have been developed. Typical examples are the addition 

of organometallic compounds to aldehydes, hydrosilylation, 

and hydrogenation of aldehydes or ketones. 2 

Among these transformations hydrogenations represent 

the most atom-efficient and environmentally benign 

methodology. In particular, transfer hydrogenation is 

a powerful strategy because of the ease of performance 

and general applicability. 3 More specifically, a broad 

scope of alcohols is available by transfer hydrogenation 

using non-toxic hydrogen donors, for example, 2-propanol 

or HCOOH/NEt3, under mild reaction conditions in 

the presence of precious metal catalysts based on Ir, Rh, 

Ru, or Ni. 4 

With regard to the upcoming catalyst developments a 

fundamental challenge is the substitution of these expensive 

and rare transition metals by less toxic, inexpensive 

and abundantly available metals such as iron. 5 Until 

now, homogeneous iron catalysts have been most frequently 

applied for carbon–carbon coupling reactions, 

such as olefin polymerizations, cross-couplings and cycloadditions 

as well as reductions of nitro compounds. 6 

However, much less attention was directed toward 

iron-catalyzed (transfer) hydrogenations, although the 

relevance of such reductions is evident even with respect 

* Corresponding author. Tel.: +49 381 1281 113; fax: +49 381 1281 

5000; e-mail: matthias.beller@catalysis.de 

0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. 

doi:10.1016/j.tetlet.2006.09.058 

Tetrahedron Letters 47 (2006) 8095–8099 

to industrial applications. To the best of our knowledge 

only the groups of Noyori, 7 Vancheesan, 8 Bianchini 9 

and Gao 10 reported the utilization of iron salts and iron 

complexes in the reduction of a,b-unsaturated carbonyl 

compounds and ketones. For tuning the activity and 

selectivity of these catalysts, oxygen and moisture sensitive 

tetradentate phosphines 9 or aminophosphines 10 

have been predominantly applied as ligands. 

Inspired by nature we thought that multidentate nitrogen 

ligands should be also suitable ligands for stabilizing 

iron as metal centre in transfer hydrogenations. In the 

past biomimetic ligand toolboxes were invented, which 

are based on natural sources or similar structural motifs, 

for example, amino alcohols, quinidines, bisoxazolines 

and porphyrins. 11 Within these potential ligands, 

porphyrins, which are involved in manifold biological 

redox processes, seemed of special interest to us due to 

their strong ability to stabilize the iron centre. 12,13 

Stimulated by our ongoing research in catalytic hydrogenations 

15 we became interested in developing new 

hydrogenation catalysts based on iron. Thus, we report 

herein for the first time a combination of iron and porphyrins 

as catalysts for the efficient reduction of various 

ketones (Scheme 1). 

In exploratory experiments, 2-propanol-based transfer 

hydrogenation of acetophenone was examined using 

an easy to adopt in situ catalyst system comprising 

Fe 3(CO) 12 and porphyrin 1a. Typically, the active catalyst 

is prepared by stirring a solution of 1 mol % iron 

source and 1 mol % 1a in 2-propanol (1.0 mL) for 16 h

8096 S. Enthaler et al. / Tetrahedron Letters 47 (2006) 8095–8099 

Scheme 1. Selection of applied porphyrins. 14 

at 65 °C. After the addition of 50 mol % base the 

mixture is heated for 5 min at 100 °C and the standard 

substrate acetophenone 4 is added. 16 

Initially, the influence of temperature and various bases 

on the reaction rate was investigated. An optimal catalyst 

activity is obtained at 100 °C (Table 1, entries 1– 

3). In general, sodium and potassium alkoxides gave 

an excellent yield of 1-phenylethanol (96–99%, Table 

1, entries 4–8). Noteworthy from a practical point of 

view is that NaOH and K 2CO 3 also led to a high product 

yield. However, in the presence of organic bases such 

as NEt3 and pyridine (Table 1, entries 10 and 11) no 

significant amount of product is formed in reasonable 

time. Diminishing the base concentration resulted in a 

decrease of 1-phenylethanol. In the absence of a base, 

no transfer of hydrogen was observed. 

Table 1. Catalytic transfer hydrogenation of acetophenone 4 

Entry Iron source Base Temperature (°C) Yield (%) a 

1 Fe3(CO)12 2-PrONa 80 56 

2 Fe3(CO) 12 2-PrONa 90 68 

3 Fe3(CO) 12 2-PrONa 100 96 

4 Fe3(CO)12 NaOH 100 98 

5 Fe3(CO)12 KOH 100 42 

6 Fe3(CO) 12 LiOH 100 5 

7 Fe3(CO) 12 K-t-OBu 100 99 

8 Fe3(CO)12 Na-t-OBu 100 97 

9 Fe3(CO)12 K2CO3 100 89 

10 Fe3(CO) 12 NEt3 100 1%) of by-products (e.g., aldol condensation 

products) are obtained. 

Next, attempts were made concerning the iron source 

(Table 2). 17 The best activity was obtained for 

Fe 3(CO) 12, FeBr 2, Fe(acac) 3 and [Et 3NH][HFe(CO) 4]. 18 

Surprisingly, no reliable correlation between the oxidation 

state and reaction rate was observed as high activity 

was detected for Fe(0)-, Fe(II)- and Fe(III)-salts. Hence, 

the formation of the active catalyst species is complete 

for the various pre-catalysts under the applied conditions. 

However, studying the dependency of conversion 

versus reaction time in the presence of Fe3(CO)12 

revealed an induction period of nearly 2 h. 

Table 2. Influence of iron sources in the transfer hydrogenation of 

acetophenone 4 

Entry Iron source Yield (%) a 

1 Fe3(CO) 12 96 

2 FeBr2 98 

3 FeCl2 90 

4 FeCl3 86 

5 Fe(acac) 2 74 

6 Fe(acac)3 97 

7 CpFe(CO)2I 44 

8 FeSO4 46 

9 [Et3NH][HFe(CO) 4] 97 

Standard reaction conditions: 0.0038 mmol in situ catalyst 

(0.0038 mmol Fe-source or 0.0013 mmol Fe3(CO)12 and 0.0038 mmol 

1a in 2.0 mL 2-propanol for 16 h at 65 °C), 0.19 mmol base, 5 min at 

100 °C, then the addition of 0.38 mmol acetophenone 4, 7 h at 100 °C. 

a 

Yield and conversion were determined by GC analysis (50 m Lipodex 

E, 95–150 °C) with diglyme as an internal standard.

In the case of Fe(acac)2 and Fe(acac)3 a favourable 

conversion was observed for the Fe(III)-salt. Comparing 

the results of FeCl 2 and FeBr 2, a small influence of the 

corresponding halide was also detected. 

Next, we focused our attention on the influence of the 

metal–ligand ratio. Even without any ligand some catalytic 

activity is obtained (54% of 5). The addition of 0.5 

or 0.2 equiv of 1a (with respect to Fe) increased the yield 

of 1-phenylethanol to 74% and 86%, respectively. The 

highest yield is obtained at a metal–ligand ratio of 1:1. 

A further increase of the number of ligand with respect 

to iron (2:1) resulted in a slight decrease of activity (89% 

of 5). 

In order to further improve the catalyst system, we 

applied different porphyrin ligands (1a–3) in the model 

reaction in the presence of 0.5 mol % Fe catalyst 

(Fe 3(CO) 12, sodium 2-propylate, 100 °C). As shown in 

Table 3, best yields were achieved with meso-substituted 

porphyrins 1b and 1e (Table 3, entries 3 and 6). Substitution 

in the meso-phenylic system of porphyrin 1b with 

electron withdrawing groups (1a, 1c, and 1d) displayed a 

decrease in activity (Table 3, entries 1, 3 and 4). 

In addition, porphyrins substituted in the b-pyrrolenic 

positions were employed in the reduction of acetophenone. 

The activity of the symmetric coproporphyrin I 

2 was to some extend lower when compared with 

meso-substituted porphyrins. The natural complex chloroprotoporphyrin 

IX Fe(III) 3 was utilized without catalysts 

pre-formation as described for all other ligands, 

and a moderate yield of 1-phenylethanol was detected 

(Table 3, entry 8). Nevertheless, complex 3 is an interesting 

catalyst for such reactions due to easier handling and 

availability. 

Table 3. Testing of different porphyrins in the transfer hydrogenation 

of acetophenone 4 

Entry Porphyrin Catalyst 

loading (mol %) 

Yield (%) a TOF (h 1 ) b 

1 1a 0.5 90 26 

2 1a 0.01 45 642 

3 1b 0.5 93 27 

4 1c 0.5 68 19 

5 1d 0.5 56 16 

6 1e 0.5 94 27 

7 2 0.5 45 13 

8 3 0.5 51 15 

Standard reaction conditions: 0.0038 mmol or 0.000038 mmol in situ 

catalyst (0.0013 mmol or 0.000013 mmol Fe3(CO)12 and 0.0038 mmol 

or 0.000038 mmol porphyrin in 2.0 mL 2-propanol for 16 h at 65 °C), 

0.19 mmol or 0.0019 mmol sodium 2-propylate, 5 min at 100 °C, then 

the addition of 0.76 mmol acetophenone 4, 7 h at 100 °C. 

a 

Conversion was determined by GC analysis (50 m Lipodex E, 95– 

150 °C) with diglyme as an internal standard. 

b 

Turnover frequencies were determined after 7 h. 

S. Enthaler et al. / Tetrahedron Letters 47 (2006) 8095–8099 8097 

Table 4. Fe-catalyzed reduction of various ketones in the presence of 

porphyrins 1b and 1e 

Entry Product 1b Yield (%) a 

1 46 72 

2 >99 >99 

3 93 95 

4 50 68 

5 92 87 

6 21 22 

7

8098 S. Enthaler et al. / Tetrahedron Letters 47 (2006) 8095–8099 

6 and 7). Comparing different substitutions on the 

phenyl ring no reliable relationship between electron 

donating and electron withdrawing substituents and 

activity was observed (Table 4, entries 1–4). Similar to 

the model reaction, in all cases conversion and yield 

were nearly identical. 

In agreement with previous findings the highest yield is 

obtained with 2-methoxyacetophenone due to the presence 

of a second coordination site. 19 

In addition to aryl alkyl ketones, we also examined more 

challenging dialkyl ketones in this iron-catalyzed transfer 

hydrogenation. Good conversion and yield (89– 

90%) were observed for both substrates applying an iron 

catalyst containing 1e as ligand. In general, ligand 1e 

gave better results compared to 1b. This effect is especially 

pronounced for the dialkyl substrates (Table 4, 

entries 8 and 9). 

In conclusion, we have demonstrated for the first time 

the successful application of in situ prepared iron 

porphyrin catalysts in the transfer hydrogenation of 

ketones. The catalyst system is easily prepared and mimics 

biologically occurring Fe complexes. Under optimized 

conditions turnover frequencies up to 642 h 1 

were achieved. The scope and limitation of the catalyst 

were demonstrated on the reduction of nine different 

ketones with good to excellent yields. 


This work has been financed by the State of Mecklenburg-Western 

Pomerania, the Bundesministerium für 

Bildung und Forschung (BMBF) and the Deutsche 

Forschungsgemeinschaft (Leibniz-award). We thank 

Mr. B. Hagemann, Mrs. C. Mewes, Mrs. M. Heyken, 

Mrs. S. Buchholz, and Dr. C. Fischer (all Leibniz-Institut 

für Katalyse e.V. an der Universität Rostock) for 

their excellent technical and analytical support. 

References and notes 

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and the easy accessibility the current price of iron is 

relatively low (approximately 300 US-dollar/t) compared 

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processes. 

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16. All experiments were carried out under an inert gas 

atmosphere (argon) with exclusion of air. For the standard 

S. Enthaler et al. / Tetrahedron Letters 47 (2006) 8095–8099 8099 

reaction procedure Fe3(CO)12 (0.0013 mmol) and porphyrin 

1a (0.0038 mmol) is dissolved in 1.0 mL 2-propanol 

and stirred for 16 h at 65 °C. Then a solution of sodium 2propylate 

(0.19 mmol) in 0.5 mL 2-propanol is added. The 

solution is stirred for 5 min at 100 °C followed by the 

addition of 0.38 mmol acetophenone 4. After 7 h at 

100 °C, the mixture is cooled to rt and filtered over a plug 

of silica gel. The conversion and yield were determined 

by GC without further purification. All synthesized 

alcohols are known compounds. Their characterization 

is done by a comparison with authentic samples. 

17. Sodium 2-propylate was chosen due to easier handling. 

18. Dahl, L. F.; Blount, J. F. Inorg. Chem. 1965, 4, 1373– 

1375. 

19. Enthaler, S.; Hagemann, B.; Erre, G.; Junge, K.; Beller, 

M. Chem. Asian J. 2006, 1, in press.



6.1.3. Biomimetic Transfer Hydrogenation of 2–Alkoxy– and 

2–Aryloxyketones with Iron Porphyrin Catalysts 

Stephan Enthaler, Björn Spilker, Giulia Erre, Man Kin Tse, Kathrin Junge, and Matthias 

Beller*, Tetrahedron 2007, submitted. 

Contributions 

Ligands 1a and 1d were synthesized by Dr. M. K. Tse. Electrochemical experiments were 

carried out by Dr. B. Spilker. 

114

Pergamon 

Tetrahedron 

TETRAHEDRON 

Biomimetic Transfer Hydrogenation of 2-Alkoxy- and 2- 

Aryloxyketones with Iron Porphyrin Catalysts 

Stephan Enthaler, Björn Spilker, Giulia Erre, Kathrin Junge, Man Kin Tse, and Matthias Beller * 

Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Str. 29a, D-18059 Rostock, Germany 

Abstract— In situ generated iron porphyrins are applied as homogeneous catalysts in the transfer hydrogenation of αsubstituted 

ketones. Using 2-propanol as hydrogen donor various hydroxyl-protected 1,2-hydroxyketones are reduced to the 

corresponding mono-substituted 1,2-diols in good to excellent yield. Under optimized reaction conditions catalyst turnover 

frequencies up to 2500 h -1 have been achieved. © 2008 Elsevier Science. All rights reserved 


The relevance of 1,2-diols is impressively shown by the 

production of ethylene and propylene glycol on multimillion-ton 

scale for the synthesis of polymers and antifreeze 

compounds. In addition, more complex 1,2-diols and 

their derivatives constitute interesting building blocks for a 

variety of biologically active compounds. 

In general, synthetic approaches to 1,2-diols are based on 

oxidative processes of olefins. Typical processes include 

the epoxidation of C=C double bonds with peracids or 

hydroperoxides and subsequent hydrolysis, and secondly 

the dihydroxylation of olefins in the presence of osmium 

catalysts (Scheme 1). 1 

R 1 

R 4 

R 2 

R 3 

Dihydroxylation 

Epoxidation Ring- 

R1 O R2 opening 

R 4 

Scheme 1. Possible approaches to 1,2-diols. 

R 3 

HO OH 

R1 R2 R4 R3 Hydrogenation 

A much less explored reaction is the transition metalcatalyzed 

reduction of 1,2-hydroxyketones. Among the 

different reductions, the transfer hydrogenation with 2propanol 

as non-toxic hydrogen donor is practical and easy 

to perform. 2,3 Until now only a few number of applications 

were reported using Rh or Ru based metal catalysts in the 

reduction of hydroxy-protected 1,2-hydroxyketones, which 

——— 

* Tel: +49-381-1281-113; Fax: +49-381-1281-5000; e-mail: matthias.beller@catalysis.de. 

R 1 

O 

R 2 

O 

R 1 

O 

R 3 R 2 

Reduction 

OR 5 

is in contrast to the well-studied reduction of 

acetophenone. 4 

A major challenge for catalytic hydrogenations is the 

substitution of expensive and rare transition metals (Ir, Rh, 

Ru) by ubiquitous available, inexpensive and less toxic 

metals. Consequently, the use of iron catalysts is especially 

desirable. 5 Up to now, homogeneous iron catalysts have 

been mostly used for carbon-carbon bond formation, such 

as olefin polymerizations, cross couplings, and 

cycloadditions as well as reduction of nitro compounds. 6 

However, much less attention was directed towards ironcatalyzed 

transfer hydrogenation. Only the groups of 

Noyori, 7 Vancheesan, 8 Bianchini, 9 and Gao 10 reported the 

utilization of iron salts and iron complexes, containing 

tetradentate phosphines 9 or aminophosphines 10 , in the 

reduction of ketones to obtain alcohols and α,β-unsaturated 

carbonyl compounds to yield α,β-saturated carbonyl 

compounds. 

More recently, we established two iron-based methods for 

the effective transfer hydrogenation of aryl alkyl as well as 

alkyl alkyl ketones utilizing 2-propanol as the hydrogen 

source. 11 On the one hand we applied a combination of iron 

salts, tridentate amines and phosphines as catalysts. 11a On 

the other hand an in situ catalyst composed of an iron salt 

and porphyrins has been used (Scheme 2). 11b Unfortunately, 

both catalyst systems faced some difficulties with αsubstituted 

alkyl aryl ketones. Herein we report for the first 

time the successful hydrogenation of α-alkoxy- and αaryloxy-substituted 

acetophenones in the presence of ironporphyrin-complexes. 

1

2 

R 

NH N 

N 

MeO 2C(H 2C) 2 

MeO 2C(H 2C) 2 

R 

R 

HN 

NH N 

N 

HN 

R 

(CH 2) 2CO 2Me 

(CH 2) 2CO 2Me 

1a R = p-Cl-C 6H 4 

1b R = C 6H 5 

1c R = p-C 6H 4NMe 3Tos 

1d R = C 6F 5 

1e R = 4-pyridyl 

HO 2C(H 2C) 2 

N Cl N 

Fe 

N 

N 

Tetrahedron 

(CH 2) 2CO 2H 

coproporphyrin I (2) chlorprotoporphyrin IX Fe (III) (3) 

Scheme 2. Selection of applied porphyrin ligands. 11b 

2. Results and Discussion 

For exploratory experiments the hydrogenation of 2methoxyacetophenone 

was used as a model reaction. 

Typically, the pre-catalyst is prepared by stirring a solution 

of 1 mol% iron salt and 1 mol% 1a in 2-propanol (1.0 mL) 

for 16 h at 65 °C. After addition of 50 mol% base the 

mixture is heated for 5 minutes at 100 °C and the substrate 

2-methoxyacetophenone 4 is added. At first, the influence 

of different iron precursors on the reaction rate was studied 

(Table 1). To our delight full conversion is obtained in all 

cases within 4 h. Obviously, the formation of the active 

catalyst is independent from the Fe-salt and is complete for 

all stated pre-catalysts under the standard conditions. 

Without any Fe present no conversion took place, also 

using FeCl2 without ligand gave only 37% yield. From a 

practical point of view we chose FeCl2 as iron source for 

further investigations. 

It is well known, that the kind and also the amount of base 

are important parameters for obtaining reasonable 

quantities of product in transfer hydrogenations. Thus, we 

investigated frequently used bases, such as NaOH, KOH 

and KO t Bu. In all cases excellent yields are achieved, 

except for LiOH and Cs2CO3 (Table 2, entries 1–9). 

Diminishing the base concentration to 5–10 mol% resulted 

in a decrease of yield of 2-methoxy-1-phenylethanol 5, 

while 25 mol% base still gave excellent yield within two 

hours. Noteworthy, in the absence of base no transfer of 

hydrogen occurred (Table 2, entry 15). In addition, 

nitrogen-containing bases (e.g. pyridine, NEt3, DBU) were 

tested, but only unsatisfactory results were attained 

(conversion: 99 

4 b) 

5 

FeCl 2 

FeCl 3 

37 

>99 

6 FeBr 2 >99 

7 FeI 2 >99 

8 Fe(acac) 2 >99 

9 Fe(acac) 3 >99 

10 FeSO 4 7H 2O >99 

11 CpFe(CO) 2I >99 

12 c) 

Fe(III)citrate H 2O >99 

13 Fe 3(CO) 12 >99 

Reaction conditions: 0.0038 mmol in situ catalyst (0.0038 mmol Fe-source 

or 0.0013 mmol Fe3(CO)12 and 0.0038 mmol 1a in 1.0 mL 2-propanol for 

16 h at 65 °C), 0.19 mmol NaOH in 0.5 mL 2-propanol, 0.38 mmol 2methoxyacetophenone 

4 in 0.5 mL 2-propanol, 4 h at 100 °C. a) Yield was 

determined by GC analysis (30 m HP Agilent Technologies 50–300 °C) 

with diglyme as internal standard. b) No ligands are added. c) Fe(III)citrate 

was recrystallized before use. 12 

On the one hand, substitution of strong coordinating 

chloride ligands by weaker BF4 - ligands via addition of 

AgBF4 was done. On the other hand activation of the 

catalyst by light irradiation (Perkin–Elmer PE300BF lamp 

with hot mirror, ~380–770 nm) has been tried. 

Surprisingly, both procedures led to complete deactivation 

of the catalysts with respect to hydrogenation reaction. 

In order to further improve the catalyst system we applied 

different porphyrin ligands (1a–3) under the optimized 

conditions, namely 0.5 mol% Fe catalyst or 0.01 mol%, 

respectively, (FeCl2 and the corresponding porphyrin in a 

ratio of 1:1), sodium hydroxide (25 mol% or 0.5 mol%) at 

100 °C (Table 3). In case of 0.5 mol% catalyst loading for 

all iron-porphyrin catalysts excellent conversion was 

attained. For 0.01 mol% catalyst loading best performance 

was achieved with the meso-substituted porphyrin 1a 

(Table 3, entry 2). Substitution at the meso-phenylic system 

of porphyrin with electron withdrawing groups (1c and 1d) 

lowered the catalyst activity. Furthermore, an excellent 

turnover frequency of 1850 h -1 was observed with a

porphyrin substituted at the β−pyrrolenic positions (Table 

3, entry 12). The complex chloroprotoporphyrin IX Fe(III) 

3 was utilized without catalysts pre-formation as described 

for all other representatives, and good turnover numbers 

were determined (Table 3, entries 13–14). Reducing the 

catalyst loading to 0.01 mol% turnover frequencies up to 

2100 h -1 were realized (Table 3, entries 1–3). 

Table 2: Influence of temperature and base in the Fe-catalyzed transfer 

hydrogenation of 2-methoxyacetophenone 4. 

O 

OMe 

FeCl 2/1a 

base, 2-PrOH, 4 h 

4 5 

Entry Base Base 

[mol%] 

Temp. 

[°C] 

OH 

OMe 

Yield [%] a) 

1 NaOH 50 100 >99 

2 

KOH 50 100 >99 

3 LiOH 50 100 49 

4 NaO i Pr 50 100 >99 

5 KO t Bu 50 100 >99 

6 b) 

NaO t Bu 50 100 >99 

7 K 2CO 3 50 100 >99 

8 Na 2CO 3 50 100 97 

9 Cs 2CO 3 50 100 37 

10 c) 

NaOH 50 25 99 

15 e) 

16 e) 

17 e) 

18 e) 

19 e) 

- - 100 99 

NaOH 50 100 >99 

Reaction conditions: 0.0038 mmol in situ catalyst (0.0038 mmol FeCl2 and 

0.0038 mmol 1a in 1.0 mL 2-propanol for 16 h at 65 °C), 0.19 mmol base 

in 0.5 mL 2-propanol, 0.38 mmol 2-methoxyacetophenone 4 in 0.5 mL 2propanol, 

4 h at described temperature. a) Yield was determined by GC 

analysis (30 m HP Agilent Technologies 50–300 °C) with diglyme as 

internal standard. b) A mixture of solvents was used t-BuOH and 2propanol 

1:4. c) Light assisted reaction, thereby only the visible range was 

applied since the ultraviolet range was shielded. d) Addition of 2 equiv. 

AgBF4 with respect to FeCl2. e) Reaction time: 2 h. 

Notably, the addition of small amounts of water (5 mol% to 

10 mol%) accelerated the transfer hydrogenation compared 

to the water-free conditions and turnover frequencies up to 

2500 h -1 were achieved. Higher amounts of water (up to 

500 mol%) hampered the reaction. 

Tetrahedron 

yield [%] 

O 

OMe 

FeCl 2/1a 

OH 

NaOH, 2-PrOH, 2 h 

4 5 

60 

50 

40 

30 

20 

10 

0 

2100 

2500 

2450 

1850 

1200 

0 5 10 25 50 500 

amount of water [mol%] 

3000 

2500 

2000 

1500 

1000 

500 

0 

OMe 

TOF [1/h] 

Figure 1. The influence of water addition on hydrogenation of 2methoxyacetophenone 

4. Reaction conditions: 0.038 μmol in situ catalyst 

(0.038 μmol FeCl2 and 0.08 μmol 1a in 1.0 mL 2-propanol for 16 h at 65 

°C), 1.9 μmol NaOH in 0.5 mL 2-propanol, the corresponding amount of 

water, 0.38 mmol substrate in 0.5 mL 2-propanol, temperature: 100 °C , 

reaction time: 2 h. a) Yield was determined by GC analysis (30 m HP 

Agilent Technologies 50–300 °C) with diglyme as internal standard. 

Under optimized conditions (vide supra), FeCl2, 1a, NaOH, 

100 °C, we compared the activity of the catalytic system 

for the reduction of acetophenone 6, orthomethoxyacetophenone 

8 and 2-methoxyacetophenone 4. 

Here, the yield of 1-phenylethanol 7, ortho-methoxy-1phenylethanol 

9 and 2-methoxy-1-phenylethanol 5 was 

monitored during the reaction. 

The attained curves are shown in Figure 2. The reduction of 

2-methoxyacetophenone proceeded without any induction 

period or deactivation process. Similar behaviour was 

observed for ortho-methoxyacetophenone, albeit a slight 

deceleration occurred after nearly 100 min. Nevertheless, 

full conversion was reached after 7 hours. In case of 

acetophenone the reduction process was significantly 

slower. After 8 hours a deactivation took place. Notably, 

the activities are in agreement with the oxidation potentials 

of the applied ketones (2-methoxyacetophenone, E0 = 213 

mV; ortho-methoxyacetophenone, E0 = 141 mV 13 ; 

acetophenone, E0 = 118 mV). 

In order to demonstrate the usefulness of our concept the 

catalyst containing ligand 1a was tested in the 

hydrogenation of several hydroxy-protected 1,2hydroxyketones 

(Table 4). 

3

4 

Tetrahedron 

Table 3: Screening of different porphyrins in the Fe-catalyzed transfer 

hydrogenation of 2-methoxyacetophenone 4. 

O 

OMe 

FeCl 2/Porphyrin 

OH 

NaOH, 2-PrOH, 2 h 

4 5 

Entry Ligand Catalyst 

loading [mol%] 

OMe 

Yield [%] a) TOF [h -1 ] b) 

1 1a 0.5 >99 >99 

2 1a 0.01 42 2100 

3 1b 0.5 >99 >99 

4 1b 0.01 30 1500 

5 1c 0.5 >99 >99 

6 1c 0.01 18 900 

7 1d 0.5 >99 >99 

8 1d 0.01 23 1150 

9 1e 0.5 >99 >99 

10 1e 0.01 24 1200 

11 2 0.5 >99 >99 

12 2 0.01 37 1850 

13 3 0.5 >99 >99 

14 3 0.01 26 1300 

Reaction conditions: 0.0019 mmol or 0.038 mmol in situ catalyst (0.0019 

mmol or 0.038 μmol FeCl2 and 0.0019 mmol or 0.038 μmol porphyrin in 

1.0 mL 2-propanol for 16 h at 65 °C), 0.095 mmol or 0.0019 mmol 

sodium hydroxide in 0.5 mL 2-propanol, 0.38 mmol 2methoxyacetophenone 

4 in 0.5 mL 2-propanol, 2 h at 100 °C. a) Yield was 

determined by GC analysis (30 m HP Agilent Technologies 50–300 °C) 

with diglyme as internal standard. b) Turnover frequencies were 

determined after 2 h. 

In general, the substrates were synthesized by reacting 2bromo 

ketones with different alcohols in the presence of 

base. 14 A first set of experiments was dedicated to the 

variation of the protecting group. Good to excellent yield 

was obtained by changing the methoxy-group by phenoxy 

substituents. Best results were achieved with the pchlorophenoxy 

substituent (Table 4, entry 2). Increasing the 

bulkiness at 2- and 6-position the conversion decreased 

significantly (Table 4, entry 4), while substitution only at 2position 

led to excellent conversion of the desired product. 

Substitution on the acetophenone skeleton by a p-methyl or 

p-methoxy group gave good to full conversion. In addition, 

indanone and pinacolin based substrates were synthesized 

and tested in this transfer hydrogenation, thereby moderate 

conversions were obtained (Table 4, entries 7 and 8). 

Unfortunately, variation of the hydroxyl protecting group to 

common acetyl and tert-butyldimethylsilyl groups 

displayed an inactivity of presented catalyst (Table 4, 

entries 11 and 12). The hydrogenation of 2-hydroxyacetophenone 

20 and 2-hydroxy-2-methyl-1-phenylpropan- 

1-one 21 were not successful since decomposition was 

observed. In addition, 2-morpholino-acetophenone 22, 

which is a promising precursor for 1,2-amino alcohols, was 

subjected to the transfer hydrogenation protocol. 

Unfortunately, no conversion was observed even if the 

reaction time was extended to 24 hours (Table 4, entry 15). 

R 1 

O 

R 2 

4 R1 = H; R2 = OMe 

100 

6 R1 = H; R2 = H 

8 R1 = 90OMe; 

R2 = H 

yield [%] 

80 

70 

60 

50 

40 

30 

20 

10 

[Fe]/1a 

Na-2-OPr, 2-PrOH, 100 °C 

R 1 

OH 

R 2 

5 R 1 = H; R 2 = OMe 

7 R 1 = H; R 2 = H 

9 R 1 = OMe; R 2 = H 

0 

0 100 200 300 400 500 600 700 

time [min] 

Figure 2. Comparative study between acetophenone 6, orthomethoxyacetophenone 

8 and 2-methoxyacetophenone 4. Reaction 

conditions: 0.0038 mmol in situ catalyst (0.0038 mmol FeCl2 and 0.0038 

mmol 1a in 1.0 mL 2-propanol for 16 h at 65 °C), 0.19 mmol base in 0.5 

mL 2-propanol, 0.76 mmol substrate in 0.5 mL 2-propanol, temperature: 

100 °C. a) Yield was determined by GC analysis (7: 50 m Lipodex E, 95– 

150 °C, 7: 50 m Lipodex E, 90–180 °C, 9: 30 m HP Agilent Technologies 

50–300 °C) with diglyme as internal standard. 

In order to get further informations about the presented 

catalytic system we carried out electrochemical 

investigations of the in situ catalysts containing ligands 1ae. 

Cyclic voltammetry has been established as a useful tool 

for studying the electrochemical properties of porphyrins 

and metalloporphyrins. 15 The measurement conditions were 

as close to the reaction conditions as possible. However, 

under strong basic conditions, no reliable measurements 

were possible, due to low catalyst solubility at room 

temperature. Therefore measurements were performed in 

the absence of base. The temperature dependence of the 

potentials according to the Nernst equation have to be 

similar for all Fe-porphyrins and should be in the range of 

20 to 30 mV between room temperature and the reaction 

temperature of 100 °C. The electrochemical analysis is 

presented in Figure 3. 

All cyclic voltammograms illustrate clearly the oxidation of 

Fe(II) to Fe(III) in the potential range above ca. 0.2 V vs. 

SCE. The small (negative) reduction currents result 

probably from Fe(III) contamination of the FeCl2 or from 

oxidation of FeCl2 from other impurities (e.g. O2). From the 

5 

7 

9

colour of the solutions (light brown to red-brown) and the 

height of oxidation current (compared to 5 mmol/L FeCl2) 

the curves result from free FeCl2 (light yellow coloured 

solution) or incomplete Fe(II)-porphyrin formation can be 

excluded. 16 

Table 4: Reduction of α-substituted ketones in the presence of 

iron catalyst containing porphyrin 1a. 

O 

OH 

FeCl 

X 

2/1a 

R 

R 

X 

4 R 

1 

R1 

4 

R 

NaOH, 2-PrOH, 100 °C, 2 h 

2 R R 3 

2 R3 Run Substrate Product conv. 

[%] 

1 

2 

3 

4 

6 

7 

8 

9 

10 

O 

O 

O 

O 

O 

O 

O 

O 

O 

O 

O 

OMe 

4 

O 

10 

11 

12 

O 

i-Pr 

15 

13 

O 

14 

O 

O 

16 

t-Bu 

i-Pr 

MeO 17 

Cl 

O Ph 

OH 

OH 

OH 

OH 

OH 

OH 

O 

O 

OMe 

5 

O 

10a 

11a 

12a 

O 

i-Pr 

OH 

13a 

O 

14a 

O 

15a 

OH 

O 

OH 

16a 

t-Bu 

i-Pr 

MeO 17 

O Ph 

Cl 

Tetrahedron 

>99 

92 

>99 a) 

97 

74 a) 

43 

48 

>99 a) 

83 a) 

11 

12 

13 

14 

15 

Ph 

O 

O 

O 

O 

O 

OAc 

18 

O 

Si 

19 

OH 

20 

OH 

21 

N 

22 

O 

Ph 

OH 

OH 

OH 

OH 

OH 

OAc 

O 

Si 

19a 

18a 

OH 

20a 

OH 

21a 

N 

O 

22a 

5 

6 

Tetrahedron 

by formation of other complexes, since 2-propanol and 

chloride ions are present in the solution, which are possible 

ligands for the axial position. During oxidation of Fe(II)- to 

Fe(III)-porphyrin one anion has to fulfil the unsaturated 

situation at the Fe(III) center analogue to compound 3 in 

Scheme 2. At the same time it has to be considered that 

Fe(II)-porphyrins can also be coordinated with two axial 

ligands (six-coordinate Fe(II)). 15,17 The small amount of 

dissolved chlorid results maybe in slower kinetics of the 

Fe(III)-porphyrin formation, seen by the reversible 

potential values (Table 5). 

Table 5: Half-wave potentials and values for reversibility. 

Compound TOF E1/2 vs. SCE / mV slope / mV 

1d 1150 326 146 

1e 1200 339 141 

1b 1500 338 152 

1a 2100 330 204 

FeCl2 - 380 205 

Ferrocene - 525 61 

Due to the influence of the axial ligand a change or 

different coordination of the porphyrins at the axial 

positions results in a shift of potential (with an excess of 

chlorid the potentials shift to lower values with higher 

reversibility). 15 The half-wave potentials for the first 

oxidation step resulting from the measurements under these 

conditions are presented in Table 5. Under conditions 

identical with those for the porphyrins the 

ferrocenium/ferrocene couple has a half-wave potential of 

525 mV and a slope of 61 mV (E1/2 = 480 mV in 0.1 mol/L 

TBA PF6 / CH2Cl2). 18 With the half-wave potentials of the 

Fe-porphyrins no correlation with the TOF can be found. In 

addition following our standard protocol the formation of 

the pre-catalyst was studied by in situ mass spectroscopy. 

After stirring FeCl2 and ligand 1a for 16 hours at 65 °C the 

corresponding iron complex 19 formed by elimination of 2 

equiv. of HCl was detected, which is in agreement with 

previous reports. 20 Unfortunately, no other catalyst 

intermediate could be unambiguously identified. Thus, the 

detailed mechanism of the Fe-based hydrogenation 

catalysts is still unclear. 

In conclusion, we have demonstrated the successful 

extension of the Fe-catalyzed transferhydrogenation to α- 

hydroxy-protected hydroxyketones. Under optimized 

conditions turnover frequencies up to 2500 h -1 were 

achieved. The scope and limitation of the catalyst were 

demonstrated on reduction of ten different ketones with 

good to excellent yields. 

3. Experimental Section 

3.1. General 

1 H and 13 C NMR spectra were recorded on Bruker 

Spectrometer 400 and 300 ( 1 H: 400.13 MHz, and 300.13 

MHz; 13 C: 100.6 MHz, and 75.5 MHz). The calibration of 

1 H and 13 C spectra was carried out either on solvent signals 

(δ CDCl3) = 7.25 and 77.0) or TMS. Mass spectra were 

recorded on an AMD 402 spectrometer. IR spectra were 

recorded as KBr pellets or Nujol mulls on a Nicolet Magna 

550. All manipulations were performed under argon 

atmosphere using standard Schlenk techniques. Unless 

specified, all chemicals are commercially available and 

used as received. 2-Propanol was used without further 

purification (purchased from Fluka, dried over molecular 

sieves). Sodium 2-propylate and sodium t-butylate were 

prepared by reacting sodium with 2-propanol or t-butanol, 

respectively, under an argon atmosphere (stock solution). 

Ketone 8 was dried over CaH2, distilled in vacuum and 

stored under argon. Substrates 18 and 19 were used without 

further purifications. Porphyrins 1a and 1d were 

synthesized according to literature protocols. 21 Fe(III)citrate 

was recrystallized from water/ethanol before use since it 

was purchased in technical grade. 

3.2. General procedure for the synthesis of substrates: 

A solution of 2-bromo ketone (10.1 mmol), phenol (10.1 

mmol), K2CO3 (15 mmol) in acetone (15 mL) was refluxed 

for 3 hours. The solvent was removed in vacuum and the 

residue dissolved in ethyl acetate / diethyl ether and washed 

with water and brine. After drying over Na2SO4 the solvent 

was removed and the crude product was purified by 

crystallization. 

2-Phenoxy-acetophenone (10): 10.1 mmol scale, flash 

column chromatography (eluent: ethyl acetate/n-hexane 

4:1), recrystallized from 2-propanol. Yield: 39% (white 

crystals). Mp = 60–61 °C. 1 H NMR (300 MHz, CDCl3) δ = 

8.02–7.98 (m, 2H); 7.64–7.58 (m, 1H); 7.53–7.46 (m, 2H); 

7.31–7.22 (m, 2H); 7.01–6.90 (m, 3H); 5.28 (s, 2H, CH2). 

13 C NMR (75.5 MHz, CDCl3): δ = 194.5; 157.9; 134.5; 

133.8; 129.5; 128.8; 128.1; 121.6; 114.7; 70.7. IR (KBr): 

3387 w; 3060 w; 2897 w; 2843 w; 2749 w; 1928 w; 1708 s; 

1599 s; 1499 s; 1480 m; 1449 m; 1433 m; 1386 w; 1341 w; 

1303 m; 1292 m; 1250 s; 1228 s; 1189 m; 1175 m; 1094 m; 

1076 m; 1028 w; 1001 m; 975 m; 921 w; 886 w; 872 m; 

751 s; 688 s; 665 m; 614 w; 584 w; 555 w; 511 m; 414 w. 

MS (EI): m/z (%) = 212 ([M + ], 26); 105 (100); 77 (43); 51 

(12). HRMS calculated for C14H14O2: 214.09883; Found: 

214.098506. 

2-(4-Chlorophenoxy)-acetophenone (11): 7.8 mmol scale, 

refluxing time: 12 h, crystallized from 2-propanol. Yield: 

73% (white plates). Mp = 87–88 °C. 1 H NMR (300 MHz, 

CDCl3) δ = 8.01–7.96 (m, 2H); 7.66–7.56 (m, 1H); 7.54– 

7.47 (m, 2H); 7.26–7.20 (m, 2H); 6.90–6.83 (m, 2H); 5.26

(s, 2H, CH2). 13 C NMR (75.5 MHz, CDCl3): δ = 194.0; 

156.6; 134.3; 134.0; 129.4; 128.9; 128.0; 126.5; 116.1; 

70.9. IR (KBr): 3375 w; 3060 w; 2901 w; 2851 w; 2737 w; 

1699 s; 1596 s; 1581 m; 1490 s; 1448 m; 1437 s; 1409 w; 

1385 w; 1338 w; 1317 w; 1289 s; 1231 s; 1172 m; 1106 m; 

1096 m; 1089 m; 1075 m; 1001 m; 983 s; 921 w; 870 w; 

830 s; 813 m; 786 w; 756 s; 701 w; 686 s; 634 w; 587 m; 

508 m; 476 w; 457 w; 441 w; 422 w; 406 w. MS (EI): m/z 

(%) = 246 ([M + ], 15); 105 (100); 77 (30). HRMS calculated 

for C14H11ClO2: 246.04421; Found: 246.044678. 

2-(2-tert-Butyl-4-methylphenoxy)-acetophenone (12): 6.0 

mmol scale, refluxing time: 12 h, crystallized from 2propanol. 

Yield: 44% (white needles). Mp = 94–95 °C. 1 H 

NMR (300 MHz, CDCl3) δ = 8.05–8.00 (m, 2H); 7.66–7.59 

(m, 1H); 7.55–7.48 (m, 2H); 7.13 (d, 1H, J = 2.26 Hz); 6.96 

(ddd, 1H, J = 8.10 Hz, J = 2.26 Hz, J = 0.75 Hz); 6.76 (d, 

1H, J = 8.22 Hz); 5.29 (s, 2H, CH2); 2.30 (s, 3H, CH3); 

1.43 (s, 9H, C(CH3)3). 13 C NMR (75.5 MHz, CDCl3): δ = 

194.5; 154.8; 138.4; 134.7; 133.7; 130.3; 128.8; 128.1; 

127.8; 127.1; 112.3; 71.0; 34.7; 29.9; 20.8. IR (KBr): 3399 

w; 3051 w; 2958 s; 2901 m; 2856 m; 2733 w; 1709 s; 1598 

m; 1581 w; 1499 s; 1448 m; 1439 m; 1404 w; 1386 m; 

1357 w; 1287 m; 1266 m; 1244 m; 1226 s; 1181 w; 1156 

w; 1107 m; 1074 w; 1020 w; 1001 m; 980 s; 930 w; 919 w; 

876 w; 861 m; 802 s; 751 s; 687 s; 655 m; 584 m; 491 m. 

MS (EI): m/z (%) = 282 ([M + ], 64); 267 (21); 249 (21); 161 

(11); 121 (13); 119 (16); 117 (14); 105 (100); 91 (33); 77 

(29). HRMS calculated for C19H22O2: 28216143; Found: 

282.162186. 

2-(2,6-Di-iso-propylphenoxy)-acetophenone (13): 5.6 

mmol scale, refluxing time: 12 h, crystallized from 2propanol. 

Yield: 34% (yellow crystals). Mp = 60–65 °C. 1 H 

NMR (300 MHz, CDCl3) δ = 8.01–7.95 (m, 2H); 7.66–7.59 

(m, 1H); 7.55–7.47 (m, 2H); 7.16 (s, 3H); 5.12 (s, 2H, 

CH2); 3.34 (sept, 2H, J = 6.91 Hz, CH); 1.25 (d, 12H, J = 

6.87 Hz, CH3). 13 C NMR (75.5 MHz, CDCl3): δ = 193.9; 

153.0; 141.6; 133.7; 128.8; 127.8; 125.2; 124.3; 76.7; 26.5; 

24.1. IR (KBr): 3442 br; 3063 w; 3028 w; 2967 s; 2868 m; 

1706 s; 1597 m; 1580 w; 1451 m; 1429 m; 1381 w; 1371 

w; 1360 m; 1334 m; 1255 m; 1227 m; 1185 s; 1163 m; 

1100 m; 1085 m; 1075 w; 1058 w; 1042 w; 1001 w; 992 w; 

972 m; 934 w; 854 w; 801 m; 763 m; 755 s; 692 m; 648 w; 

617 w; 586 w; 556 w; 521 w; 472 w; 434 w. MS (EI): m/z 

(%) = 296 ([M + ], 10); 176 (83); 161 (100); 147 (20); 133 

(16); 105 (59); 91 (44); 77 (28); 43 (11). HRMS calculated 

for C20H24O2: 296.17708; Found: 296.176483. 

2-Phenoxy-2,3-dihydro-1H-inden-1-one (14): 9.5 mmol 

scale, refluxing time: 16 h, Yield: 56% (off-white crystals). 

Mp = 75–78 °C. 1 H NMR (300 MHz, CDCl3) δ = 7.85 (d, 

1H, J = 7.72 Hz); 7.67 (dt, 1H, J = 7.44 Hz, J = 1.13 Hz); 

7.50–7.41 (m, 2H); 7.37–6.99 (m, 2H); 7.10–6.99 (m, 3H); 

5.09 (dd, 1H, J = 7.54 Hz, J = 4.52 Hz, CH); 3.73 (dd, 1H, 

J = 7.54 Hz, J = 16.95 Hz, CH2); 3.19 (dd, 1H, J = 16.95 

Hz, J = 4.33 Hz, CH2). 13 C NMR (75.5 MHz, CDCl3): δ = 

201.7; 157.9; 150.6; 135.9; 134.6; 129.5; 128.2; 126.7; 

Tetrahedron 

124.6; 121.7; 115.7; 77.8; 34.1. IR (KBr): 3413 br; 3063 w; 

3039 w; 3028 w; 2916 w; 2906 w; 1716 s; 1608 m; 1597 

m; 1587 m; 1493 m; 1474 m; 1464 m; 1431 w; 1325 w; 

1299 m; 1276 m; 1250 m; 1233 s; 1208 w; 1174 w; 1156 

w; 1080 m; 1070 m; 1038 w; 1020 w; 1005 m; 956 w; 913 

m; 889 w; 753 s; 725 m; 691 m; 618 w; 607 w; 502 w; 455 

w. MS (EI): m/z (%) = 224 ([M + ], 53); 131 (100); 103 (32); 

94 (11); 77 (25). HRMS calculated for C15H12O2: 

224.08318; Found: 224.083160. 

3,3-Dimethyl-1-phenoxybutan-2-one (15): 11.2 mmol 

scale, refluxing time: 16 h. Yield: 92% (off-white crystals). 

Mp = 33–36 °C. 1 H NMR (300 MHz, CDCl3) δ = 7.32– 

7.24 (m, 2H); 7.00–6.93 (m, 1H); 6.91–6.84 (m, 2H); 4.87 

(s, 2H, CH2); 1.25 (s, 9H, C(CH3)3). 13 C NMR (75.5 MHz, 

CDCl3): δ = 209.4; 158.0; 129.5; 121.4; 114.6; 68.8; 43.1; 

26.3. IR (KBr): 3420 br; 3105 w; 3065 w; 3043 w; 2973 m; 

2931 m; 2872 w; 2846 w; 2747 w; 1721 s; 1678 w; 1599 

m; 1587 m; 1494 s; 1461 m; 1446 m; 1431 m; 1386 w; 

1365 m; 1329 w; 1291 m; 1234 s; 1179 m; 1152 w; 1113 

m; 1078 w; 1052 s; 1026 w; 1000 m; 990 s; 962 m; 935 w; 

880 m; 825 m; 766 s; 759 s; 693 m; 587 w; 545 w; 522 m. 

MS (EI): m/z (%) = 192 ([M + ], 33); 108 (13); 77 (26); 57 

(100); 41 (16). HRMS calculated for C12H16O2: 192.11448; 

Found: 192.114302. 

2-Phenoxy-4´-methylacetophenone (16): 9.4 mmol scale, 

refluxing time: 16 h, crystallized from 2-propanol. Yield: 

51% (colourless crystals). Mp = 62–63 °C. 1 H NMR (300 

MHz, CDCl3) δ = 7.94–7.88 (m, 2H); 7.33–7.24 (m, 4H); 

7.02–6.91 (m, 3H); 5.25 (s, 2H, CH2); 2.43 (s, 3H, CH3). 

13 C NMR (75.5 MHz, CDCl3): δ = 194.1; 158.0; 144.8; 

132.1; 129.54; 129.48; 128.2; 121.6; 114.6; 70.7; 21.8. IR 

(KBr): 3441 br, 3063 w; 3036 w; 2919 w; 2902 w; 2847 w; 

1695 s; 1606 s; 1587 m; 1576 m; 1498 s; 1455 w; 1433 m; 

1411 m; 1385 w; 1292 m; 1254 m; 1236 s; 1208 m; 1192 

m; 1174 m; 1149 w; 1124 w; 1113 w; 1092 m; 1075 w; 

1044 w; 1027 w; 1001 m; 979 m; 885 m; 871 m; 816m; 

749 s; 711 w; 690 m; 609 w; 584 m; 551 w; 517 w; 498 w; 

461 w. MS (EI): m/z (%) = 226 ([M + ], 15); 119 (100); 91 


Found: 226.099202. 

2-Phenoxy-4´-methoxyacetophenone (17): 8.7 mmol 

scale, refluxing time: 16 h, crystallized from 2-propanol. 

Yield: 74% (off-white needles). Mp = 54–55 °C. 1 H NMR 

(300 MHz, CDCl3) δ = 7.96–7.89 (m, 2H); 7.24–7.16 (m, 

2H); 6.93–6.84 (m, 5H); 5.13 (s, 2H, CH2); 3.80 (s, 3H, 

CH3). 13 C NMR (75.5 MHz, CDCl3): δ = 193.1; 164.0; 

158.0; 130.5; 129.0; 127.6; 121.5; 114.7; 114.0; 70.7; 55.5. 

IR (KBr): 3442 br; 3056 w; 3006 w; 2955 w; 2934 w; 2840 

w; 1960 m; 1687 s; 1653 w; 1601 s; 1511 m; 1497 s; 1459 

m; 1419 w; 1368 m; 1314 m; 1265 s; 1245 m; 1226 s; 1171 

s; 1154 w; 1116 m; 1075 m; 1032 m; 976 s; 884 m; 835 m; 

789 m; 769 m; 751 s; 691 m; 631 w; 608 m; 582 m; 543 w; 

511 w; 492 w. MS (EI): m/z (%) = 242 ([M + ], 10); 135 


Found: 242.093706. 

7

8 

Tetrahedron 

2-Oxo-2-phenylethyl acetate (18): 2–Hydroxy–1– 

phenylethanone (8.0 mmol) was dissolved in 

dichloromethane (10 mL) and acetic anhydride (8.0 mmol), 

pyridine (8.5 mmol) and 4–dimethylaminopyridine (0.08 

mmol) were added. The solution was stirred for 2 hours 

under refluxing conditions. The mixture was washed with 

water and brine. After drying over Na2SO4 the solvent was 

removed and yellow crystals were obtained. Yield: 83%. 

Mp = 48–50 °C. 1 H NMR (300 MHz, CDCl3) δ = 7.93– 

7.88 (m, 2H); 7.63–7.56 (m, 1H); 7.51–7.44 (m, 2H); 5.34 

(s, 2H, CH2); 2.22 (s, 3H, CH3). 13 C NMR (75.5 MHz, 

CDCl3): δ = 192.0; 170.3; 134.1; 133.8; 128.7; 127.6; 65.9; 

20.4. IR (KBr): 3460 w; 3375 w; 3064 m; 2982 w; 2937 m; 

1741 s; 1699 s; 1599 m; 1581 w; 1493 w; 1452 m; 1423 m; 

1374 m; 1321 w; 1280 m; 1244 s; 1228 s; 1185 m; 1087 m; 

1077 m; 1047 m; 1020 m; 996 m; 970 m; 849 m; 812 m; 

757 m; 688 m; 634 m; 597 m; 566 m; 483 m; 443 w; 414 

w. MS (EI): m/z (%) = 178 ([M + ], 1); 105 (100); 77 (34); 

51 (10); 43 (14). HRMS calculated for C15H14O3: 

178.06245; Found: 178.063004. 

2-(tert-Butyldimethylsilyloxy)-1-phenylethanone (19): 2– 

Hydroxy–1–phenylethanone (8.0 mmol) was dissolved in 

dichloromethane (10 mL) and imidazole (8.5 mmol) was 

added. After stirring for 10 minutes at room temperature 

tert–butyldimethylchlorosilane (8.5 mmol) was added 

dropwise, while rapidly a white precipitate was formed. 

The mixture was stirred for 5 hours at room temperature. 

Water was added and the organic layer was washed with 

water and brine. After removal of the solvent a yellow oil 

was obtained. Yield: 89%. 1 H NMR (300 MHz, CDCl3) δ = 

7.95–7.89 (m, 2H); 7.61–7.42 (m, 3H); 4.93 (s, 2H, CH2); 

0.94 (s, 9H, C(CH3)3); 0.13 (s, 6H, Si(CH3)2). 13 C NMR 

(75.5 MHz, CDCl3): δ = 197.4; 134.9; 132.2; 128.6; 127.9; 

67.4; 25.8; 18.5; -5.4. IR (KBr): 2953 w; 2929 m; 2885 w; 

2856 m;1705 s; 1599 m; 1581 w; 1472 m; 1449 m; 1390 w; 

1362 w; 1288 m; 1254 m; 1229 m; 1151 s; 1025 w; 1002 

m; 974 s; 939 w; 834 s; 777 s; 753 s; 712 m; 688 s; 670 s. 

MS (EI): m/z (%) = 251 ([M + +H], 16); 193 (66); 181 (10); 

149 (12); 135 (13); 105 (100); 75 (73). 

2-Morpholino-acetophenone (22): Morpholine (62 mmol) 

was added dropwise to a solution of 2–bromoacetophenone 

(7.5 mmol) in THF (15 mL). A white precipitate was 

formed while the mixture was refluxed for one day. An 

aqueous solution of NaHCO3 was added. After extraction 

with diethyl ether the organic layer was washed with 

aqueous solution of NaOH and dried over Na2SO4. The 

crude product was purified by flash column 

chromatography (eluent: ethyl acetate/n–hexane 1:1) to 

yield a brownish oil. Yield: 89%. 1 H NMR (300 MHz, 

CDCl3) δ = 8.02–7.97 (m, 2H); 7.60–7.55 (m, 1H); 7.50– 

7.43 (m, 2H); 3.83 (s, 2H, C(O)CH2); 3.79 (m, 4H, CH2); 

2.62 (m, 4H, CH2). 13 C NMR (75.5 MHz, CDCl3): δ = 

172.0; 160.9; 131.9; 129.6; 128.1; 67.1; 66.4; 64.4; 41.7; 

40.6. IR (KBr): 3415 w; 3060 m; 2970 m; 2852 m; 2762 w; 

1924 w; 1674 s; 1598 s; 1558 m; 1493 w; 1449 s; 1384 s; 

1314 m; 1300 m; 1271 s; 1230 m; 1176 m; 1113 s; 1069 m; 

1047 w; 1022 m; 1006 m; 981 w; 931 w; 876 w; 840 w; 

812 w; 788 w; 757 w; 722 m; 693 w; 674 w; 593 w; 547 w; 

449 w. MS (EI): m/z (%) = 205 ([M + ], 2); 100 (100); 77 

(18); 56 (21). HRMS calculated for C12H15O2N: 205.10973; 

Found: 205.109149. Rf (ethyl acetate/n-hexane 1:1) = 0.14. 

General procedure for the catalytic transfer 

hydrogenation: In a 10 mL Schlenk tube, the in situ 

catalyst (0.0038 mmol) is prepared stirring a solution of 

FeCl2 (0.0038 mmol) and porphyrin (0.0038 mmol) in 1.0 

mL 2-propanol for 16 h at 65 °C. The pre-catalyst system is 

reacted with sodium hydroxide (0.38 mmol in 0.5 mL 2propanol) 

and 2-methoxyacetophenone (0.38 mmol in 0.5 

mL 2-propanol) for 2 h at 100 °C. The solution is cooled to 

r.t. and filtered over a plug of silica. The conversion was 

measured by GC without further manipulations and the 

products were isolated by column chromatography or 

crystallization. 

2-Phenoxy-1-phenylethanol (10a): Mp = 48–50 °C (white 

crystals). 1 H NMR (300 MHz, CDCl3) δ = 7.40–7.15 (m, 

7H, Ph); 6.92–6.80 (m, 3H, Ph); 5.03 (dd, 1H, J = 8.67 Hz, 

J = 3.20 Hz, CH); 4.03–3.88 (m, 2H, CH2); 2.55 (br, 1H, 

OH). 13 C NMR (75.5 MHz, CDCl3): δ = 158.3; 139.6; 

129.5; 128.5; 128.2; 126.3; 121.3; 114.6; 73.2; 72.5. IR 

(KBr): 3302 br; 3060 w; 3028 w; 2932 w; 2877 w; 1598 s; 

1585 M; 1498 s; 1453 M; 1389 w; 1346 w; 1303 m; 1292 

m; 1249 s; 1196 m; 1172 m; 1152 w; 1098 m; 1078 m; 

1067 m; 1046 m; 1028 m; 995 w; 917 m; 884 w; 863 m; 

792 w; 754 s; 701 s; 692 s; 637 m; 615 m; 594 m; 541 m; 

512 m. MS (EI): m/z (%) = 214 ([M + ], 12); 108 (100); 94 

(46); 79 (60); 51 (18). HRMS calculated for C14H14O2: 

214.09883; Found: 214.098407. 

2-(4-Chlorophenoxy)-1-phenylethanol (11a): Mp = 46– 

48 °C (white crystals). 1 H NMR (300 MHz, CDCl3) δ = 

7.48–7.19 (m, 7H); 6.87–6.80 (m, 2H); 5.11 (dd, 1H, J = 

8.48 Hz, J = 3.38 Hz, CH); 4.08–3.95 (m, 2H, CH2); 2.70 

(br, 1H, OH). 13 C NMR (75.5 MHz, CDCl3): δ = 157.0; 

139.4; 129.4; 128.6; 128.3; 126.2; 126.1; 115.8; 72.6; 72.5. 

IR (KBr): 3313 br; 3059 w; 3032 w; 2933 w; 2875 w; 1596 

m; 1581 m; 1491 s; 1453 m; 1388 w; 1345 w; 1290 m; 

1242 s; 1196 w; 1169 m; 1093 m; 1066 m; 1039 m; 1006 

m; 914 m; 864 w; 825 m; 801 m; 749 m; 700 m; 671 m; 

633 w; 616 m; 559 w; 507 m. MS (EI): m/z (%) = 248 

([M + ], 21); 142 (34); 128 (70); 107 (100); 91 (12); 79 (31). 

HRMS calculated for C14H13ClO2: 248.05986; Found: 

248.059204. 

2-(2-tert-Butyl-4-methylphenoxy)-1-phenylethanol 

(12a): Mp = 61–64 °C (colourless crystals). 1 H NMR (300 

MHz, CDCl3) δ = 7.53–7.32 (m, 5H, Ph); 7.13 (d, 1H, J = 

2.13 Hz, Ph); 6.98 (ddd, 1H, J = 8.29 Hz, J = 2.26 Hz, J = 

0.75 Hz, Ph); 6.78 (d, 1H, J = 8.09 Hz, Ph); 5.21 (dd, 1H, J 

= 7.35 Hz, J = 4.71 Hz, CH); 4.18–4.08 (m, 2H, CH2); 2.67 

(br, 1H, OH); 2.31 (s, 3H, CH3); 1.41 (s, 9H, C(CH3)3). 13 C 

NMR (75.5 MHz, CDCl3): δ = 155.0; 139.9; 137.7; 129.9; 

128.5; 128.1; 127.7; 127.1; 126.3; 112.2; 73.5; 72.9; 34.7;

30.0; 20.8. IR (KBr): 3570 m; 3030 w; 2994 w; 2856 m; 

2917 m; 2867 m; 1605 w; 1581 w; 1497 s; 1451 s; 1406 m; 

1389 m; 1359 m; 1327 w; 1294 m; 1264 m; 1228 s; 1198 

m; 1151 m; 1095 m; 1060 m; 1033 s; 1001 w; 934 w; 911 

m; 881 w; 854 m; 809 m; 764 m; 702 s; 624 w; 602 w; 592 

w; 553 w; 516 w; 493 w. MS (EI): m/z (%) = 284 ([M + ], 

27); 164 (31); 149 (100); 121 (18); 107 (17); 91 (21); 77 


284.176978. 

2-(2,6-Di-iso-propylphenoxy)-1-phenylethanol (13a): Mp 

= 67–69 °C (colourless crystals). 1 H NMR (300 MHz, 

CDCl3) δ = 7.46–7.26 (m, 5H); 7.09 (s, 3H); 5.16 (dd, 1H, 

J = 7.53 Hz, J = 4.40 Hz, CH); 3.92–3.82 (m, 2H, CH2); 

3.29 (sept, 2H, J = 6.91 Hz, CH(CH3)2); 3.10 (br, 1H); 1.22 

(dd, 12H, J = 6.90 Hz, J = 1.29 Hz). 13 C NMR (75.5 MHz, 

CDCl3): δ = 152.4; 141.6; 139.8; 128.4; 128.0; 126.1; 

125.8; 124.9; 79.3; 73.3; 26.4; 24.04; 24.00. IR (KBr): 

3064 m; 3030 m; 2963 s; 2927 s; 2868 m; 1604 w; 1589 w; 

1454 s; 1384 m; 1362 m; 1327 m; 1255 m; 1182 s; 1100 m; 

1047 s; 1020 s; 936 w; 913 m; 861 w; 834 w; 802 m; 755 

m; 700 s; 682 w; 623 w; 590 w; 527 w. MS (EI): m/z (%) = 

298 ([M + ], 8); 178 (51); 163 (100); 107 (15); 91 (16); 77 


298.192353. 

2-Phenoxy-2,3-dihydro-1H-inden-1-ol (14a): colourless 

crystals. During the reaction a mixture of diastereomers 

were formed in a ratio of 1:3 (D1:D2). 1 H NMR (400 MHz, 

CDCl3) δ = 7.56–6.93 (m); 5.34 (d, 1H, J = 4.12 Hz, D1); 

5.28 (d, J = 5.22 Hz, D2); 5.08–5.02 (m, 1H, D2); 4.98– 

4.89 (m, 1H, D1); 3.53 (dd, 1H, J = 16.37 Hz, J = 6.92 Hz, 

D1); 3.20 (d, 2H, J = 4.40 Hz, D2); 2.98 (dd, 1H, J = 16.37 

Hz, J = 5.32 Hz, D1); 2.81 (br, OH). 13 C NMR (100.6 

MHz, CDCl3): δ = 157.7; 142.4; 139.5; 139.2; 129.6; 

129.5; 128.9; 128.6; 127.3; 125.1; 125.0; 124.8; 124.5; 

121.7; 121.6; 121.0; 115.8; 115.5; 85.4; 80.3; 75.6; 36.4; 

35.9. IR (Nujol): 3182 w; 2723 w; 1598 m; 1585 m; 1496 

m; 1459 s; 1377 s; 1291 m; 1250 s; 1207 w; 1170 w; 1155 

w; 1118 m; 1073 w; 1050 w; 1020 w; 1001 w; 879 w; 849 

w; 779 w; 746 s; 723 m; 693 m; 639 w; 511 w; 413 w. MS 

(EI): m/z (%) = 226 ([M + ], 19); 133 (100); 115 (21); 103 

(21); 94 (61); 77 (29); 65 (11). HRMS calculated for 

C15H14O2: 226.09883; Found: 226.099031. 

3,3-Dimethyl-1-phenoxybutan-2-ol (15a): Mp = 31–33 °C 

(colourless crystals). 1 H NMR (300 MHz, CDCl3) δ = 

7.33–7.24 (m, 2H); 7.00–6.88 (m, 3H); 4.14 (dd, 1H, J = 

9.23 Hz, J = 2.45 Hz, CH); 3.86 (m, 2H, CH2); 2.35 (br, 

1H, OH); 1.01 (s, 9H, C(CH3)3). 13 C NMR (75.5 MHz, 

CDCl3): δ = 158.6; 129.5; 121.1; 114.6; 77.2; 69.3; 33.5; 

26.0. IR (KBr): 3272 br; 3035 w; 2954 s; 2876 m; 1601 m; 

1586 m; 1499 s; 1459 m; 1393 w; 1366 m; 1338 m; 1296 

m; 1245 s; 1190 w; 1174 m; 1152 w; 1095 m; 1079 m; 

1044 m; 1020 m; 1020 m; 1005 m; 992 w; 942 w; 926 m; 

902 m; 895 m; 821 w; 754 s; 692 m; 598 w; 572 w; 513 m; 

402 w. MS (EI): m/z (%) = 194 ([M + ], 26); 119 (10); 108 

(63); 94 (100); 87 (19); 77 (22); 69 (14); 57 (24); 41 (17). 

Tetrahedron 

HRMS calculated for C12H18O2: 194.13013; Found: 194. 

129870. 

2-Phenoxy-1-(4´-methylphenyl)ethanol (16a): Mp = 50– 

51 °C (colourless crystals). 1 H NMR (300 MHz, CDCl3) δ 

= 7.34–7.14 (m, 6H); 6.98–6.85 (m, 3H); 5.05 (dd, 1H, J = 

8.64 Hz, J = 3.36 Hz, CH); 4.04 –3.97 (m, 2H, CH2); 2.87 

(br, 1H, OH); 2.34 (s, 3H, CH3). 13 C NMR (75.5 MHz, 

CDCl3): δ = 158.3; 137.8; 136.7; 129.5; 129.2; 126.2; 

121.1; 114.5; 73.2; 72.3; 21.1. IR (KBr): 3297 br; 3027 w; 

2912 w; 2880 w; 1932 w; 1599 m; 1586 m; 1514 m; 1498 

s; 1460 m; 1388 m; 1340 m; 1293 m; 1250 s; 1195 m; 1180 

m; 1172 m; 1151 w; 1090 s; 1045 m; 1021 m; 995 w; 975 

w; 943 w; 916 m; 886 w; 868 m; 838 w; 815 m; 756 s; 716 

w; 693 m; 616 w; 597 m; 575 w; 537 m; 513 m; 487 w; 464 

w; 403 w. MS (EI): m/z (%) = 228 ([M + ], 6); 121 (100); 

108 (68); 105 (15); 65 (11). HRMS calculated for 

C15H16O2: 228.11448; Found: 228.114429. 

2-Phenoxy-1-(4´-methoxyphenyl)ethanol (17a): yellow 

oil. 1 H NMR (300 MHz, CDCl3) δ = 7.32–7.15 (m, 4H); 

6.92–6.77 (m, 5H); 4.98 (dd, 1H, J = 8.67 Hz, J = 3.39 Hz, 

CH); 4.00–3.87 (m, 2H, CH2); 3.73 (s, 3H, CH3); 2.77 (br, 

1H). 13 C NMR (75.5 MHz, CDCl3): δ = 159.4; 158.3; 

131.7; 129.5; 127.5; 121.2; 114.6; 113.9; 73.2; 72.1; 55.3. 

IR (KBr): 3440 br; 3072 w; 3044 w; 2999 w; 2929 m; 2831 

w; 1728 w; 1612 m; 1600 m; 1587 m; 1514 s; 1497 s; 1456 

m; 1303 m; 1245 s; 1174 m; 1154 w; 1114 w; 1080 m; 

1036 m; 912 w; 867 w; 832 m; 755 m; 692 m; 639 w; 596 

w; 552 w; 511 w. MS (EI): m/z (%) = 244 ([M + ], 2); 137 

(100); 121 (10); 108 (23); 94 (12); 77 (21). HRMS 

calculated for C15H16O3: 244.10940; Found: 244.109218. 

3.3. Electrochemical measurements 

The electrochemical workstation is composed of an 

Autolab PGSTAT 10 potentiostat from ECO Chemie and a 

P-450 PC with GPES 4.9 software. A three-electrode 

arrangement with a platinum microelectrode (25 µm 

diameter) as the working electrode, a saturated calomel 

electrode (SCE) as reference electrode and a platinum 

counter electrode (16 mm 2 area) was used. All potentials in 

the following are cited against SCE. All measurements 

were carried out in 2-PrOH at room temperature. As 

supporting electrolyte we used 0.1 mol/L tetra-nbutylammonium 

tetrafluoraborate. Due to the low solubility 

at r.t. all solutions of porphyrins with FeCl2 were saturated 

solutions. For some porphyrins (e.g. compound 3) 

solubility was too low to see any currents. Reversibility 

was determined by plotting E vs. log[(Ia-I)/I-Ic] for the 

nearly linear range of the forward scan and determining the 

slope for the quasi-reversible electrode reactions. Anodic 

diffusion current (Ia) and cathodic diffusion current (Ic) are 

determined from the results of a sigmoidal fit with 

Microcal Origin 7.5. 

Acknowledgments 

9

10 

Tetrahedron 

We thank Mrs. S. Buchholz, and Dr. C. Fischer (both 

Leibniz–Institut für Katalyse e.V. an der Universität 

Rostock) for excellent analytical assistance and Prof. 

Jeroschewski for general discussions. Generous financial 

support from the state of Mecklenburg–Western Pomerania 

and the BMBF as well as the Deutsche 

Forschungsgemeinschaft (Leibniz–price) are gratefully 

acknowledged. 

Note and References 

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Wiley, New York, 1994; (b) Cornils B.; Herrmann, W. A. (Eds.) 

Applied Homogeneous Catalysis with Organometallic Compounds, 

Wiley-VCH, Weinheim, 1996; (c) Jacobsen, E. N.; Pfaltz, A.; 

Yamamoto, H. (Eds.), Comprehensive Asymmetric Catalysis, 

Springer, Berlin, 1999; (d) Kitamura, M.; Noyori, R. in Murahashi, 

S.-I. (Ed.) Ruthenium in Organic Synthesis, Wiley-VCH, Weinheim, 

2004; (e) Beller, M.; Bolm, C. (Eds.), Transition Metals for Organic 

Synthesis, Wiley-VCH, Weinheim, 2 nd Ed. 2004; (f) J.-E. Bäckvall 

(Ed.), Modern Oxidation Methods, Wiley-VCH, Weinheim, 2004. 

2. (a) Zassinovich, G.; Mestroni, G.; Gladiali, S. Chem. Rev. 1992, 51, 

1051-1069; (b) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 

97-102; (c) Gladiali, S.; Mestroni, G. in Beller, M.; Bolm, C. (Eds.), 

Transition Metals for Organic Synthesis, Wiley-VCH, Weinheim, 2 nd 

Ed. 2004, 145-166; (d) Blaser, H.-U.; Malan, C.; Pugin, B.; Spindler, 

F.; Studer, M. Adv. Synth. Catal. 2003, 345, 103-151; (e) Gladiali, S.; 

Alberico, E. Chem. Soc. Rev. 2006, 35, 226–236; (f) Samec, J. S. M.; 

Bäckvall, J.-E.; Andersson, P. G.; Brandt, P. Chem. Soc. Rev. 2006, 

35, 237–248. 

3. Selected recent examples of transfer hydrogenations: (a) Schlatter, A.; 

Kundu, M. K.; Woggon, W.-D. Angew. Chem. Int. Ed. 2004, 43, 

6731–6734; (b) Xue, D.; Chen, Y.-C.; Cui, X.; Wang, Q.-W.; Zhu, J.; 

Deng, J.-G. J. Org. Chem. 2005, 70, 3584–3591; (c) Wu, X.; Li, X.; 

King, F.; Xiao, J. Angew. Chem. Int. Ed. 2005, 44, 3407–3411; (d) 

Hayes, A. M.; Morris, D. J.; Clarkson, G. J.; Wills, M. J. Am. Chem. 

Soc. 2005, 127, 7318–7319; (e) Baratta, W.; Chelucci, G.; Gladiali, 

S.; Siega, K.; Toniutti, M.; Zanette, M.; Zangrando, E.; Rigo, P. 

Angew. Chem. Int. Ed. 2005, 44, 6214–6219; (f) Enthaler, S.; 

Jackstell, R.; Hagemann, B.; Junge, K.; Erre, G.; Beller, M. J. 

Organomet. Chem. 2006, 691, 4652–4659; (g) Enthaler, S.; 

Hagemann, B.; Bhor, S.; Anilkumar, G.; Tse, M. K.; Bitterlich, B.; 

Junge, K.; Erre, G.; Beller, M. Adv. Synth. Catal. 2007, accepted. 

4. (a) Cheung, F. K.; Hayes, A. M.; Hannedouche, J.; Yim, A. S. Y.; 

Wills, M. J. Org. Chem. 2005, 70, 3188-3197; (b) Matharu, D. S.; 

Morris, D. J.; Kawamoto, A. M.; Clarkson, G. J.; Wills, M. Org. Lett. 

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US-dollar per troy ounce) due to the widespread abundance of iron in 

earth´s crust and the easy accessibility. Furthermore, iron is an 

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6.2. Transfer hydrogenation of prochiral ketones with ruthenium catalysts 

6.2.1. Efficient transfer hydrogenation of ketones in the presence of 

ruthenium N–heterocyclic carbene catalysts 

Stephan Enthaler, Ralf Jackstell, Bernhard Hagemann, Kathrin Junge, Giulia Erre and 

Matthias Beller*, J. Organomet. Chem. 2006, 691, 4652–4659. 

Contributions 

Imidazolium salts 1, 2, 5, 6, 8 and 9 were synthesized by Dr. R. Jackstell and Imidazolium 

salts 11 and 12 were a chemical gift by solvent innovation. 

125

Abstract 

Efficient transfer hydrogenation of ketones in the presence 

of ruthenium N-heterocyclic carbene catalysts 

Stephan Enthaler, Ralf Jackstell, Bernhard Hagemann, Kathrin Junge, 

Giulia Erre, Matthias Beller * 

Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Strasse 29a, 18059 Rostock, Germany 

Received 27 April 2006; received in revised form 7 July 2006; accepted 13 July 2006 

Available online 27 July 2006 

Novel ruthenium carbene complexes have been in situ generated and tested for the transfer hydrogenation of ketones. Applying 

Ru(cod)(methylallyl)2 in the presence of imidazolium salts in 2-propanol and sodium-2-propanolate as base, turnover frequencies up 

to 346 h 1 have been obtained for reduction of acetophenone. A comparative study involving ruthenium carbene and ruthenium phosphine 

complexes demonstrated the higher activity of ruthenium carbene complexes. 

Ó 2006 Elsevier B.V. All rights reserved. 

Keywords: Ruthenium; Homogeneous catalysis; Transfer hydrogenation; N-heterocyclic carbenes; Ketones 


Journal of Organometallic Chemistry 691 (2006) 4652–4659 

The preparation of alcohols has become an important 

field of activity for transition metal catalyzed reactions 

[1]. Within the different catalytic approaches developed, 

for instance addition of organometallic reagents to carbonyl 

compounds, hydroxylation of olefins, functionalization 

reactions of epoxides, the hydrogenation of ketones 

or aldehydes is the most powerful tool with respect to 

industrial applications. In particular, transfer hydrogenations 

represent a potent strategy, because of high atom efficiency, 

no need of pressure, and economic as well as 

environmental advantages [2]. In more detail, a broad 

scope of alcohols is accessible by transfer hydrogenation 

using non-toxic hydrogen donors under mild reaction conditions 

in the presence of various metal catalysts, such as 

Ir, Rh or Ru [2d]. Noteworthy, a prerequisite for achieving 

high activity and selectivity is the fine tuning of the metal 

catalyst by introduction of ligands. So far the development 

of new ligands for catalytic reductions focused predominantly 

on phosphines and amines. 

* Corresponding author. Tel.: +49 381 1281 0; fax: +49 381 1281 5000. 

E-mail address: matthias.beller@ifok-rostock.de (M. Beller). 

0022-328X/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved. 

doi:10.1016/j.jorganchem.2006.07.013 

www.elsevier.com/locate/jorganchem 

More recently carbene ligands found increasing interest 

for exploiting new catalytic reactions [3]. Stable N-heterocyclic 

carbenes (NHC) were first introduced in the early 

1990’s by Arduengo et al. [4]. Since the mid 1990’s Herrmann 

et al. [5] and then the groups of Bertrand [6], Blechert 

[7], Cavell [8], Fürstner [9]. Glorius [10], Grubbs [11], 

Nolan [12] and others [13] demonstrated the catalytic 

potential of NHC metal complexes. In this context we 

reported that palladium carbene complexes are excellent 

catalysts for different coupling reactions of aryl halides 

and telomerizations [14]. 

With regard to transfer hydrogenations different carbene 

or carbene-phosphine-systems containing Rh [15], Ir 

[15,16], Ru[17] and Ni [18] have been reported. Excellent 

turnover frequencies up to 120,000 h 1 were reported by 

the groups of Baratta and Herrmann applying a ruthenium-carbene-phosphine-catalysts 

[19]. However, for 

reduction of a typical substrate, e.g. acetophenone, with 

phosphine-free ruthenium-carbene catalysts lower turnover 

frequencies (TOF 333 h 1 ) [17e] were achieved in comparison 

to iridium (500 h 1 ) [16c] and rhodium systems 

(583 h 1 ) [15b]. Due to the economical benefit of ruthenium 

metal compared to rhodium or iridium and the 

advantages of phosphine-free systems, it is an important

goal to search for more active ruthenium carbene catalysts. 

Herein, we report the application of novel in situ prepared 

ruthenium carbene catalysts in the reduction of different 

ketones. 

2. Results and discussion 

S. Enthaler et al. / Journal of Organometallic Chemistry 691 (2006) 4652–4659 4653 

Based on our experience in the synthesis of carbene 

ligands and their application in homogeneous catalysis, 

we became interested in demonstrating the usefulness of 

carbene-complexes in ruthenium-catalyzed transfer hydrogenations 

[20]. From a practical point of view the application 

of in situ prepared catalysts has significant advantages. 

Thus, we used a small library of various imidazolium salts 

(Scheme 1, 1–12) as carbene precursors. In exploratory 

experiments, 2-propanol-based transfer hydrogenation of 

acetophenone was examined. In order to ensure complete 

formation of the active catalyst a 2-propanol solution of 

1 mol% ruthenium-source and 1 mol% 1,3-bis(2,6-di-i-propylphenyl)-imidazolium 

chloride (1) is stirred in the presence 

of 5 mol% sodium 2-propylate for 16 h at 65 °C. 

Initial investigations showed a crucial effect on reactivity 

by using different ruthenium sources such as [RuCl 2- 

(C 6H 6)] 2,Ru 3(CO) 12, and Ru(cod)(methylallyl) 2 in combination 

with imidazolium salt 1 (Table 1). Best conversion 

and yield are obtained for Ru(cod)(methylallyl)2/1 at 

100 °C (Table 1, entry 8). Noteworthy, there is a significant 

temperature effect on the reaction rate (Table 1, entries 5–8). 

N + 

N 

N + 

N 

N + 

Cl - 

Br - 

N + 

N 

N + 

N 

N + 

It is well-known that transfer hydrogenations are sensitive 

to the nature of the base. Thus, the influence of sodium 

2-propylate, potassium tert-butylate, potassium carbonate 

and sodium hydroxide on selectivity and conversion was 

investigated. In all cases excellent selectivity (>99%) is 

N + 

- - 

BF4 BF4 N 

1 2 3 4 

Cl - 

5 6 7 8 

Cl 

N 

(CH2) 2 

Cl 

N 

N 

N 

- Cl- Br- Br- 9 10 11 12 

N + 

N 

N + 

Cl 

Cl - 

Scheme 1. Selection of imidazolium salts. 

Table 1 

Screening of various ruthenium sources and yield-temperature dependency 

for the transfer hydrogenation of acetophenone (13) a 

O 

[Ru]/(1), Na-2-OPr 

2-PrOH, 1h 

N + 

N 

N + 

N 

N + 

Cl - 

Tos - 

OH 

13 13a 

Entry Source Temperature (°C) Yield (%) b 

1 [RuCl2(C6H6)] 2 90 9 

2 [RuCl2(C6H6)]2 100 80 

3 Ru3(CO)12 90 40 

4 Ru3(CO)12 100 16 

5 Ru(cod)(methylallyl) 2 70 2 

6 Ru(cod)(methylallyl)2 80 43 

7 Ru(cod)(methylallyl)2 90 55 

8 Ru(cod)(methylallyl) 2 100 >99 

a 6 

Reaction conditions: in situ catalyst: 1.3 · 10 mol Ru3(CO) 12, 

1.9 · 10 6 mol [RuCl2(C6H6)] 2 or 3.8 · 10 6 mol Ru(cod)(methylallyl) 2, 

3.8 · 10 6 mol imidazolium salt 1 and 1.9 · 10 5 mol Na–2-OPr in 2.0 mL 

2-propanol for 16 h at 65 °C, addition of 3.8 · 10 4 mol acetophenone 

(13), reaction 1 h at described temperature. 

b 

Conversion is determined by GC analysis (50 m Lipodex E, 95–200 °C) 

with diglyme as internal standard.

4654 S. Enthaler et al. / Journal of Organometallic Chemistry 691 (2006) 4652–4659 

observed. Best conversion after 1 h at 100 °C are obtained 

in the presence of sodium 2-propylate (>99%) and potassium 

tert-butylate (95%). However, poor yields of 1-phenylethanol 

are achieved with potassium carbonate (53%). 

Interestingly, sodium hydroxide, one of the most common 

bases for transfer hydrogenation, induced only low conversion 

(62%). By increasing the amount of base a further 

acceleration of reaction rate is recorded, while no reaction 

occurred in the absence of base. 

Next, the influence of the ligand concentration was 

investigated by variation of the metal to ligand-ratio. When 

increasing the equivalents of ligand per metal a negative 

effect on the reaction rate is observed (Table 2). We assume 

a catalyst deactivation by more than one carbene ligand, 

due to suppressing the metal hydride formation or blocking 

the active binding site for the substrate. However, 1 equiv. 

Table 2 

Influence of metal-ligand-ratio on the reduction of acetophenone (13) 

O 

Ru(cod)methylallyl 2/(1), Na-2-OPr 

2-PrOH, 100 ˚C 

of ligand is necessary for achieving good conversion. 

Hence, transfer hydrogenations in absence of the carbene 

gave only moderate yield (Table 2, entry 1). 

The stability of metal carbene complexes against moisture 

and oxygen has been documented [13]. Thus, the addition 

of water (10 mol%) to the reaction mixture decreased 

only slightly the conversion to 73% (TOF: 73 h 1 ). Even 

in the presence of 100 mol% of water the catalyst showed 

significant activity (TOF: 54 h 1 ). 

To classify the potential of our catalytic system we compared 

Ru(cod)(methylallyl)2/1 with Ru(cod)(methylallyl)2/ 

PPh3 and Ru(cod)(methylallyl)2/PCy3 (Fig. 1). More 

specifically, we studied the behaviour of Ru(cod)(methylallyl)2/1 

and Ru(cod)(methylallyl)2/PPh3 by monitoring the 

conversion at different reaction times. The results showed 

similar catalytic behaviour at the beginning of the reaction. 

OH 

13 13a 

Entry Carbene:metal Substrate:metal Base:metal Time (h) Yield (%) c 

1 a 

2 a 

3 a 

4 a 

5 b 

6 b 

7 b 

TOF (h 1 ) d 

0 100 5 1 41 41 

1 100 5 1 >99 99 

2 100 5 1 61 61 

10 100 5 1 57 57 

1 5000 100 12 83 346 

2 5000 100 12 81 338 

10 5000 100 12 67 279 

a 6 

Reaction conditions: in situ catalyst: 3.8 · 10 mol Ru(cod)(methylallyl)2, 3.8 · 10 6 mol imidazolium salt 1 and 1.9 · 10 5 mol Na–2-OPr in 2.0 mL 

2-propanol for 16 h at 65 °C, addition of 3.8 · 10 4 mol acetophenone (13), reaction temperature 100 °C. 

b 7 

Reaction conditions: in situ catalyst: 9.7 · 10 mol Ru(cod)(methylallyl)2, 9.7 · 10 7 mol imidazolium salt 1 and 9.7 · 10 5 mol Na–2-OPr in 5.0 mL 

2-propanol for 16 h at 65 °C, addition of 4.85 · 10 3 mol acetophenone (13), reaction temperature 100 °C. 

c 

Conversion is determined by GC analysis (50 m Lipodex E, 95–200 °C) with diglyme as internal standard. 

d Turnover frequency = mol product/(mol catalyst · time), determined after 12 h. 

yield (%) 

100 

80 

60 

40 

20 

0 

O 

Carben (1) 

PPh3 

PCy3 

Ru(cod)(methylallyl) 2 /(1) or PPh 3, 

Na-2-OPr 

OH 

2-PrOH, 100 ˚C 

13 13a 

0 2 4 6 8 10 12 

time (h) 

Fig. 1. Comparative study using imidazolium salt 1 and PPh3 as ligands. Note: Reaction conditions: in situ catalyst: 9.7 · 10 7 mol Ru(cod)(methylallyl)2, 

9.7 · 10 7 mol imidazolium salt 1 or PPh3 and 9.7 · 10 5 mol Na-2-OPr in 5.0 mL 2-propanol for 16 h at 65 °C, addition of 4.85 · 10 3 mol acetophenone 

(13), reaction at 100 °C. Conversion is determined by GC analysis (50 m Lipodex E, 95–200 °C) with diglyme as internal standard.

However, during the reaction a higher deactivation rate of 

the PPh3-system is detected, which resulted in a lower yield 

of 1-phenylethanol after 12 h (68% vs 83%). The 

Ru(cod)(methylallyl)2/PCy3 yielded comparable amounts 

of 1-phenylethanol to Ru(cod)(methylallyl)2/1. 

As shown in Table 3 we examined 12 examples out of 

the growing number of carbene precursors (1–12) under 

the previously optimized conditions for the transfer hydrogenation 

of acetophenone (13). In order to estimate differences 

between the various carbene precursors we applied 

low catalyst loadings (0.02 mol%) at 100 °C. After 12 h 

average turnover frequencies up to 346 h 1 are achieved 

for the preparation of 1-phenylethanol applying ligand 1. 

Summarizing the activities of 4,5-dihydroimidazolium 

salts, no pronounced influence is observed by variation of 

substitutents at the nitrogen atoms (2,6-di-iso-propylphenyl 

or mesitylene groups) or by changing the anion of the 

imidazolium salt (Table 3, entries 2–4). On the other hand 

by introduction of methyl groups in the 4,5-position of the 

imidazolium unit a depletion of activity is monitored 

(Table 3, entries 5 and 6). 

In general, application of N-alkyl carbenes led to a 

lower activity compared to N-aryl carbenes (Scheme 1, 8– 

12). In the presence of 1-ethyl-3-methylimidazolium bromide 

([EMIM]Br, 11) and 1-butyl-3-methylimidazolium 

bromide ([BMIM]Br, 12), which are usually used as ionic 

liquids [21], the recorded yields were lower (Table 3, entries 

11 and 12). 

Table 3 

Variation of imidazolium salts in the transfer hydrogenation of acetophenone 

(13) a 

O 

Ru(cod)(methylallyl) 2/(1-12), Na-2-OPr 

2-PrOH, 100 ˚C, 12h 

OH 

13 13a 

Entry Imidazolium salt Yield (%) b 


TOF (h 1 ) c 

TON d 

1 1 83 346 4150 

2 2 75 313 3750 

3 3 68 283 3400 

4 4 73 304 3650 

5 5 53 221 2650 

6 6 61 254 3050 

7 7 62 258 3100 

8 8 67 279 3350 

9 9 77 320 3850 

10 10 69 288 3450 

11 11 54 225 2700 

12 12 38 158 1900 

a 7 

Reaction conditions: in situ catalyst: 9.7 · 10 mol Ru(cod)(methylallyl)2, 

9.7 · 10 7 mol imidazolium salt and 9.7 · 10 5 mol Na-2-OPr in 

5.0 mL 2-propanol for 16 h at 65 °C, addition of 4.85 · 10 3 mol acetophenone 

(13), reaction for 12 h at 100 °C. 

b 

Conversion is determined by GC analysis (50 m Lipodex E, 95–200 °C) 

with diglyme as internal standard. 

c 

Turnover frequency = mol product/(mol catalyst · time), determined 

after 12 h. 

d 

Turnover number = mol product/mol catalyst, determined after 12 h. 

In order to demonstrate the usefulness of the catalysts in 

a more general manner we employed the catalyst system 

Ru(cod)(methylallyl)2/1 in the transfer hydrogenation of 

nine aromatic and aliphatic ketones (Table 4). 

In general, all substrates were hydrogenated with excellent 

chemoselectivity (>99%). Best activity (TOF up to 

338 h 1 ) is achieved with dialkyl ketones (Table 4, entries 

Table 4 

Scope and limitations of Ru(cod)(methylallyl)2/1-system-catalyzed ketone 

reduction a 

O 

OH 

Ru(cod)(methylallyl) 2/(1), Na-2-OPr 

R 1 

R 2 

14-22 

2-PrOH, 100 ˚C, 12h 

R 1 

R 2 

14a-22a 

Entry Compound Ketone Conversion (%) b TOF (h 1 ) c 

1 14 O 

2 15 

3 16 

4 17 

5 18 

6 19 

7 20 

8 21 

9 22 

Cl 

MeO 

H 3C 

O 

O 

OMe 

O 

O 

O 

O 

O 

O 

68 [96] 285 

41 171 

62 [92] 258 

68 [97] 283 

67 [93] 281 

Cl 2 6 

40 166 

77 321 

81 338 

a 7 

Reaction conditions: in situ catalyst: 9.7 · 10 mol Ru(cod)(methylallyl)2, 

9.7 · 10 7 mol imidazolium salt 1 and 9.7 · 10 5 mol Na-2-OPr in 

5.0 mL 2-propanol for 16 h at 65 °C, addition of 4.85 · 10 3 mol ketone, 

reaction for 12 h at 100 °C. 

b 

Conversion is determined by GC analysis (14 (25 m Lipodex E, 

100 °C), 15 (50 m Lipodex E, 90–105 °C), 16 (25 m Lipodex E, 80–180 °C), 

17 (30 m HP Agilent Technologies 50–300 °C), 18 (25 m Lipodex E, 90– 

180 °C), 19 (50 m Lipodex E, 90–180 °C), 20–22 (30 m HP Agilent Technologies 

50–300 °C)) with diglyme as internal standard. In brackets the 

conversion after 24 h is given. 

c 

Turnover frequency = mol product/(mol catalyst · time), determined 

after 12 h.


8 and 9). In comparison, para-substituted acetophenones 

containing an electron-withdrawing group (Table 4, entry 

1) showed better conversion than para-substituted substrates 

with an electron-donating group (Table 4, entry 

2). Noteworthy, by changing the electron-donating group 

from para- toortho-position a significant increase of the 

yield is detected (Table 4, entries 2 and 4). We assume 

for 17 a possible second coordination site at the metal center. 

No major change in activity is observed for substitution 

adjacent to the carbonyl group by an ethyl group, 

whereas introduction of a chloromethyl deactivated the 

catalyst (Table 4, entries 5 and 6). Moderate activity is 

monitored when increasing the bulkiness next to the active 

center by a cyclopropyl group (Table 4, entry 7). 

Finally, we were interested in mechanistic aspects. In 

general, for transition metal catalyzed transfer hydrogenation 

two mechanisms are accepted, designated as direct 

hydrogen transfer, via formation of a six-membered cyclic 

transition state composed of donor, metal and acceptor, 

and the hydridic route which shows two possible pathways, 

the monohydride or dihydride mechanism. In more detail, 

formation of a monohydride-metal-complex promoted an 

exclusive hydride transfer from carbon (donor) to carbonyl 

carbon (acceptor) (Scheme 2, pathway A), whereas a 

hydride transfer from carbon (donor) to carbonyl carbon 

(acceptor) as well as to the carbonyl oxygen (acceptor) 

was proposed for a dihydride-metal-complex formation 

(Scheme 2, pathway B). Indications for both pathways 

were published by Bäckvall et al. and other groups, when 

following the hydride transfer catalyzed by various metal 

complexes [22]. 

Mechanistic studies have been mostly published for catalysts 

containing phosphines, amines or cyclopentadienyls 

as ligands [22a]. For transition metal complexes containing 

carbene ligands Faller and Crabtree described investigations 

on an iridium dicarbene system [16c]. They assumed 

O 

[M-H*] 

O 

D 

D 

H 

O 

*H 

pathway A pathway B 

OH 

O H 

O 

-acetone H* 

*H 

-acetone 

Ru(cod)(methylallyl) 2/1, 

Na-2-OPr-d 7 

2-PrOH-d 8, 100 ˚C 

O 

a monohydride mechanism, because the hydride is mainly 

transferred in the 1-position of acetophenone. So far there 

is no mechanistic investigation known in transfer hydrogenations 

applying Ru carbene catalysts. 

Reaction of ketone 20 (‘‘radical clock’’-substrate) with 

2-propanol in the presence of 1 mol% Ru(cod)(methylallyl) 

2/1 gave only the corresponding cyclopropyl phenyl 

alcohol (>99% by 1 H NMR). Apparently, there is no 

radical induced reduction [23]. Owing to this a radical 

reduction mechanism promoted by sodium alkoxides can 

be also excluded, whereby the transition metal plays only 

a marginal role [24]. This assumption is also confirmed 

by performing the reduction of acetophenone (13) in the 

presence of base and in the absence of ruthenium catalyst. 

Here, no reduction product was detected. 

Next, we followed the transfer of hydrogen from the 

donor molecule into the product by applying a deuterated 

donor [25]. The catalytic precursor is generated by stirring 

a solution of 2-propanol-d8, Ru(cod)(methylallyl)2 and imidazolium 

salt 1 in the presence of sodium 2-propanolate-d7 

for 16 h at 65 °C. Then, acetophenone (13) was added and 

the solution was stirred for 30 min at 100 °C. As main 

product (>99%) 23 was observed by 1 H NMR (Scheme 

3) [26]. The result showed an exclusive transfer of the deuterium 

into the carbonyl group, so that no C–H activation 

on the substrate occurred under the described conditions. 

Furthermore, this result rules out enol formation in the catalytic 

cycle [27]. 

To clarify the transfer of hydrogen from the hydrogen 

donor into the substrate the reaction was run with 2-propanol-d 

1 (hydroxy-group deuterated) as solvent/donor and 

sodium 2-propylate as base. In the transfer hydrogenation 

of acetophenone (13) we obtained a mixture of two different 

deuterated 1-phenylethanols (Scheme 2, 24a and 24b). 

Here, a scrambling of the transferred proton and deuteride 

is found (24a and 24b = 1:1). In conclusion the non-specific 

[H-M-H*] 

Scheme 2. Comparison of monohydride and dihydride mechanism for transfer hydrogenations. 

Ru(cod)(methylallyl) 2/1, 

Na-2-OPr 

2-PrOD, 100 ˚C 

23 13 

24a 24b 

>99% 50% 50% 

Scheme 3. Deuterium incorporation into acetophenone catalyzed by Ru(cod)(methylallyl) 2/1-system in the presence of base. 

O 

H 

D 

OH 

H* 

+ 

O 

D 

OH* 

H 

50% 50% 

H

migration is in agreement with the dihydride mechanism, 

implying a formation of metal dihydride species in the catalytic 

cycle [2d]. 

3. Summary 

We demonstrated the successful application of in situ 

prepared ruthenium catalysts containing carbene ligands 

in the transfer hydrogenation of various ketones. In the 

reduction of acetophenone (13) turnover frequencies up 

to 346 h 1 were found for a catalyst system containing 

Ru(cod)(methylallyl)2/1,3-bis(2,6-di-i-propylphenyl)-imidazolium 

chloride (1). Mechanistic experiments indicated 

the transfer of hydrogen from the donor molecule into 

the substrate via a dihydride mechanism. 

4. Experimental section 

4.1. General 

All manipulations were performed under argon atmosphere 

using standard Schlenk techniques. Unless specified, 

all chemicals are commercially available and used as 

received. Sodium 2-propylate was prepared by reacting 

sodium with 2-propanol under an argon atmosphere. 2- 

Propanol was used without further purification (purchased 

from Fluka, dried over molecular sieves). Imidazolium 

salts 1, 2, 5, 6, 8 and 9 were synthesized according to the 

published protocols [4,28]. Imidazolium salts 11 and 12 

were a gift by Solvent Innovation. Imidazolium salts 3, 4, 

7 and 10 are commercially available by Strem. All ketones 

were dried over CaH 2, distilled in vacuum and stored under 

argon, except ketones 17 and 19, which were cycled with 

vacuum-argon and stored under argon. 

4.2. General procedure for catalytic transfer hydrogenation 

of ketones 

In a 10 mL Schlenk tube, the in situ catalyst (9.7 · 

10 7 mol) was prepared by stirring a solution of 

Ru(cod)(methylallyl) 2 (9.7 · 10 7 mol), imidazolium salt 

(9.7 · 10 7 mol) and sodium 2-propylate (4.85 · 10 6 mol) 

in 1.0 mL 2-propanol for 16 h at 65 °C. After addition of 

the corresponding ketone (4.85 · 10 3 mol) and the internal 

standard diglyme in 4.0 mL 2-propanol the Schlenk tube 

was sealed and the reaction mixture was heated to 100 °C. 

After 12 h the conversion was measured by GC without further 

purification. In the case of 1 H NMR determination of 

the yield, the solvent was removed in vacuum and the residue 

was dissolved in CDCl3 and submitted to 1 H NMR. 

4.3. Procedure for transfer hydrogenation of acetophenone 

with 2-propanol-d8 as hydride source 


In a 10 mL Schlenk tube, Ru(cod)(methylallyl) 2 (3.8 · 

10 6 mol), imidazolium salt 1 (3.8 · 10 6 mol) and sodium 

2-propylate-d 7 (1.9 · 10 5 mol, prepared by reacting 

sodium with 2-propanol-d8) was solved in 1.0 mL 2-propanol-d8 

and stirred for 16 h at 65 °C. After addition of the 

acetophenone (13) (3.8 · 10 4 mol) in 2.0 mL 2-propanold8 

the reaction mixture was heated to 100 °C for 30 min. 

The solution was cooled to r.t. and filtrated over a plug 

of silica. The conversion was determined by 1 H NMR. 

4.4. Procedure for transfer hydrogenation of acetophenone 

with 2-propanol-d1 as hydride source 

In a 10 mL Schlenk tube, Ru(cod)(methylallyl)2 (3.8 · 

10 6 mol), imidazolium salt 1 (3.8 · 10 6 mol) and sodium 

2-propylate (1.9 · 10 5 mol, prepared by reacting sodium 

with 2-propanol) was solved in 1.0 mL 2-propanol-d 1 (deuterium 

fixed as hydroxyl proton) and stirred for 16 h at 

65 °C. The reaction mixture was heated to 100 °C for 

10 min after addition of the acetophenone (13) (3.8 · 

10 4 mol) in 2.0 mL 2-propanol-d1. (To avoid side effects 

reaction was not run to full conversion.) The solution 

was cooled to r.t. and filtrated over a plug of silica. The solvent 

was removed in vacuum and the residue was solved in 

CDCl 3. The conversion was determined by 1 H NMR. 

4.5. Product characterization 

The obtained alcohols are known compounds. They 

were characterized by comparison with authentic samples 

and mass spectroscopy (Agilent Technologies 6890N, 

MSD 5973) or 1 H NMR (Bruker ARX-400). Product 

13a: m/z (%) = 122 (M + , 21); 107 (72); 79 (100); 51 (34); 

43 (36); 39 (13); 32 (15). Product 14a: m/z (%) = 156 

(M + , 26); 141 (100); 121 (14); 113 (33); 103 (9); 77 (85); 

51 (12); 43 (22). Product 15a: m/z (%) = 152 (M + , 24); 

137 (100); 134 (32); 119 (20); 109 (48); 94 (38); 91 (34); 77 

(46); 65 (31); 51 (16); 43 (37); 39 (21). Product 16a: m/z 

(%) = 136 (M + , 32); 121 (100); 117 (14); 91 (94); 77 (53); 

65 (29); 51 (16); 43 (57); 39 (23). Product 17a: m/z 

(%) = 152 (M + , 31); 137 (100); 134 (20); 119 (10); 109 

(46); 94 (29); 91 (16); 77 (28); 65 (12); 43 (13). Product 

18a: m/z (%) = 152 (M + , 11); 107 (100); 79 (79); 51 (13). 

Product 19a: m/z (%) = 156 (M + , 3); 107 (100); 91 (7); 79 

(67); 77 (50); 51 (19). Product 20a: 1 H NMR (400 MHz, 

CDCl3) d (ppm) = 0.34 (1H, m); 0.44 (1H, m); 0.51 (1H, 

m); 0.58 (1H, m); 1.00 (1H, m); 2.31 (1H, s); 3.98 (1H, d, 

J = 8.16 Hz); 7.24 (3H, m); 7.99 (1H, d, J = 7.52 Hz). 

Product 21a: m/z (%) = 128 (M + , 17); 110 (34); 95 (18); 

81 (100); 67 (71); 55 (78); 41 (46). Product 22a: m/z 

(%) = 102 (M + , 3); 87 (26); 57 (100); 45 (83); 41 (53). 


This work has been financed by the State of Mecklenburg-Pomerania 

and the Bundesministerium für Bildung 

und Forschung (BMBF). We thank Mrs. C. Voss, Mrs. 

C. Mewes, Mrs. M. Heyken, Mrs. S. Buchholz and Dr. 

C. Fischer (all Leibniz-Institut für Katalyse e.V.) for their


excellent technical and analytical support. Solvent Innovation 

is gratefully thanked for a chemical gift. 

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6.2. Transfer hydrogenation of prochiral ketones with ruthenium catalysts 

6.2.2. New Ruthenium Catalysts for Asymmetric Transfer Hydrogenation 

of prochiral Ketones 

Stephan Enthaler, Bernhard Hagemann, Santosh Bhor, Gopinathan Anilkumar, Man Kin Tse, 

Bianca Bitterlich, Kathrin Junge, Giulia Erre, and Matthias Beller*, Adv. Synth. Catal. 2007, 

349, 853–860. 

Contributions 

Ligands 3a–3e were synthesized by Dr. S. Bhor, Dr. G. Anilkumar, Dr. M. K. Tse and B. 

Bitterlich. The experiments stated in table 4 entries 2 (cat. A), 3 (cat. B) and 6 (cat. A and 

cat. B) were carried out by Dr. B. Hagemann. 

134

New Ruthenium Catalysts for Asymmetric Transfer 

Hydrogenation of Prochiral Ketones 

DOI: 10.1002/adsc.200600475 

Stephan Enthaler, a Bernhard Hagemann, a Santosh Bhor, a Gopinathan Anilkumar, a 

Man Kin Tse, a Bianca Bitterlich, a Kathrin Junge, a Giulia Erre, a 

and Matthias Beller a, * 

a Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany 

Fax: (+49)-381-1281-5000; e-mail: matthias.beller@catalysis.de 

Received: September 15, 2006; Revised: February 5, 2007 

Abstract: Tridentate N,N,N-pyridinebisimidazolines 

have been studied as new ligands for the enantioselective 

transfer hydrogenation of prochiral ketones. 

High yields and excellent enantioselectivity up to 

> 99% ee have been achieved with an in situ generated 

catalytic system containing dichlorotris(triphenylphosphine)ruthenium 

and 2,6-bis-([4R,5R]-4,5diphenyl-4,5-dihydro-1H-imidazol-2-yl)-pyridine 

(3a) in the presence of sodium isopropoxide. 

Keywords: asymmetric transfer hydrogenation; ketones; 

phosphines; ruthenium; tridentate nitrogen 

ligands 

Enantiomerically pure alcohols have a wide range of 

applications, for example, building blocks and synthons 

for pharmaceuticals, agrochemicals, polymers, 

syntheses of natural compounds, auxiliaries, ligands 

and key intermediates in organic syntheses. [1] Within 

the different molecular transformations to chiral alcohols, 

transition metal-catalyzed reactions offer efficient 

and versatile strategies, such as addition of organometallic 

compounds to aldehydes, hydrosilylation, 

and hydrogenation of prochiral ketones. [2] From 

an economic and environmental point of view the 

asymmetric hydrogenation, in particular the transfer 

hydrogenation, represents a powerful tool for their 

synthesis because of its high atom economy and 

safety advantages. [3] Here, Noyori s ruthenium-based 

catalysts comprising chiral tosylated diamines constitute 

state-of-the-art transfer hydrogenation systems. 

[3d,4] Based on this seminal work an increasing 

number of ruthenium catalysts with chiral bidentate 

N,N-ligands were developed in the last decade. [3] Significantly 

fewer systems are known in which transfer 

of chiral information is promoted by tridentate ligands. 

[5,6] Up to now only a limited number of auspicious 

tridentate nitrogen-containing N,N,N ligands 

COMMUNICATIONS 

were established in the field of transfer hydrogenation. 

For example (R)-phenyl-ambox (1) [5] and different 

pyridinebisoxazoline (pybox) ligands (2) [6] have 

been applied for the reduction of acetophenone 

(Scheme 1). 

Scheme 1. N,N,N-Tridentate ligands. 

Recently, we reported the synthesis of a new class 

of chiral tridentate amines. [7] The preparation and 

tunability of these pyridinebisimidazolines (3) (socalled 

pybim ligands, Scheme 1) are easier and more 

flexible compared to the popular pyboxes, making the 

former a suitable ligand tool box for various asymmetric 

transformations. To date there is no report on 

the performance of these ligands in hydrogenation reactions. 

The resemblance between pybim (3) and 

pybox (2) stimulated our research to study the potential 

of this class of ligands in the transfer hydrogenation 

of aromatic and aliphatic ketones. 

In exploratory experiments, isopropyl alcohol-based 

transfer hydrogenation of acetophenone was examined 

using a simple in situ catalyst system composed 

of [RuCl 2ACHTUNGTRENUNG(C 6H 6)] 2, 2,6-bis-([4R,5R]-4,5-diphenyl-4,5- 

Adv. Synth. Catal. 2007, 349, 853 – 860 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 853


dihydro-1H-imidazol-2-yl)-pyridine (3) and triphenylphosphine. 

To ensure complete formation of the 

active catalyst and avoid an induction period the reaction 

mixture was heated for 10 min at 100 8C in the 

presence of base followed by addition of acetophenone. 

First, studies for optimizing the reaction conditions 

were carried out with 1 mol% of pre-catalyst 

and 5 mol% of base. It is well-known that transfer hydrogenations 

are sensitive to the nature of the base. 

Thus, the influence of different bases on selectivity 

and conversion was investigated initially (Table 1). 

Best results were obtained for sodium isopropoxide 

and K 2CO 3 with conversions up to 95% and enantiomeric 

excesses up to 94% (Table 1, entries 1 and 8). 

Interestingly, NaOH and KOH the most commonly 

used bases for transfer hydrogenations gave only 

moderate enantioselectivity (78 % and 80%, Table 1, 

entries 3 and 4). In addition, we tested some organic 

nitrogen-containing systems such as DBU, DABCO, 

NEt 3, NACHTUNGTRENUNG(i-Pr) 2Et and pyridine, but only with NACHTUNGTRENUNG(i- 

Pr) 2Et did we obtain significant amounts of product 

in a reasonable time (Table 1, entry 10). Next, the 

concentration of sodium isopropoxide was varied at 

different temperatures. As expected, the increase of 

the amount of base led to an acceleration of reaction 

rate; however, this was accompanied by an unacceptable 

decrease of enantioselectivity (Table 1, entries 13– 

15). In contrast, improved ee is obtained by reducing 

the amount of base to a ruthenium-to-base ratio of 1 

to 0.5 (Table 1, entries 16 and 17). Notably, in the absence 

of base the transfer of hydrogen did not occur. 

Based on these results we investigated the behavior 

of the metal precursor. 

Applying different ruthenium sources such as 

[RuCl 2ACHTUNGTRENUNG(PPh 3) 3], [RuHClACHTUNGTRENUNG(PPh 3) 3], [8] RuCl 3·x H 2O, 

Ru 3(CO) 12 and RuACHTUNGTRENUNG(cod)(methylallyl) 2, lower conversion 

and/or poor selectivity were achieved. Nevertheless, 

[RuCl 2ACHTUNGTRENUNG(PPh 3) 3] showed an enantiomeric excess of 

> 99 %, which is to our knowledge the highest enantioselectivity 

in this model reaction for a chiral tridentate 

ligand (Table 1, entry 17). However, a slight 

excess of pybim 3a, 3 equivs. with respect to 1 equiv. 

Table 1. Transfer hydrogenation of acetophenone in the presence of pybim ligand 3a and different bases. [a] 

Entry Base Base:Metal Temp. [8C] Conv. [%] [b] 

Stephan Enthaler et al. 

ee [%] [b] 

1 NaO-i-Pr 5 100 80 94 (S) 

2 KO-t-Bu 5 100 99 9 (S) 

3 NaOH 5 100 79 78 (S) 

4 KOH 5 100 85 80 (S) 

5 LiOH 5 100 72 80 (S) 

6 K 3PO 4 5 100 65 70 (S) 

7 K 2HPO 4 5 100 19 96 (S) 

8 K 2CO 3 5 100 95 93 (S) 

9 Cs 2CO 3 5 100 45 67 (S) 

10 NACHTUNGTRENUNG(i-Pr) 2Et 5 100 18 90 (S) 

11 NaO-i-Pr 5 60 93 84 (S) [c] 

12 NaO-i-Pr 5 80 91 83 (S) [d] 

13 NaO-i-Pr 5 90 91 88 (S) 

14 NaO-i-Pr 50 90 98 87 (S) 

15 NaO-i-Pr 250 90 99 44 (S) 

16 NaO-i-Pr 0.5 100 88 95 (S) 

17 NaO-i-Pr 0.5 100 96 >99 (S) [e] 

18 NaO-i-Pr 0.5 110 58 84 (S) 

[a] 6 

Reaction conditions: in situ catalyst A {1.9 ”10 mol [RuCl2ACHTUNGTRENUNG(C6H6)] 2, 3.8 ” 10 6 mol ligand 3a, 3.8 ” 10 6 mol PPh3}; addition 

of the corresponding base: entries 1–13: 1.9 ” 10 5 mol, entry 14: 1.9 ” 10 4 mol, entry 15: 9.5 ”10 4 mol and for entries 

16–18: 1.9 ” 10 6 mol in 2.0 mL isopropyl alcohol, 10 min at corresponding temperature then addition of 3.8 ” 10 4 

mol acetophenone, 1 h at corresponding temperature. 

[b] 

Conversion and ee were determined by chiral GC (50 m Lipodex E, 95–2008C) analysis with diglyme as internal standard. 

[c] 

Reaction time 14 h. 

[d] 

Reaction time 4 h. 

[e] 6 

In situ catalyst B {3.8 ”10 mol [RuCl2ACHTUNGTRENUNG(PPh3) 3], 1.14 ” 10 5 mol 3a}. Conversion was determined by GC (30 m HP Agilent 

Technologies 50–300 8C) with diglyme as internal standard and ee was determined by chiral HPLC (Chiralcel OB-H, 

eluent: n-hexane/ethanol, 99:1, flow rate: 2 mL min 1 ) analysis. 

854 www.asc.wiley-vch.de 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Synth. Catal. 2007, 349, 853 – 860

Ruthenium Catalysts for Asymmetric Transfer Hydrogenation 

of ruthenium, was necessary to achieve high enantioselectivity. 

To compare the difference of catalyst 

system A and catalyst system B, we investigated the 

conversion-time and the enantioselectivity-time dependency 

(Scheme 2). No significant change of enan- 

Scheme 2. Conversion-time and enantioselectivity-time behavior 

of catalyst A and catalyst B. Reaction conditions: in 

situ catalyst A (1.9 ” 10 6 mol [RuCl 2ACHTUNGTRENUNG(C 6H 6)] 2, 3.8 ” 10 6 mol 

ligand 3a, 3.8 ” 10 6 mol PPh 3)orin situ catalyst B (3.8 ” 

10 6 mol [RuCl 2ACHTUNGTRENUNG(PPh 3) 3], 1.14 ” 10 5 mol 3a); addition of 

sodium isopropoxide (1.9”10 6 mol) in 2.0 mL 2-propanol, 

10 min at 100 8C then addition of 3.8 ”10 4 mol acetophenone, 

reaction temperature: 100 8C. Conversion was determined 

by GC (30 m HP Agilent Technologies 50–300 8C) 

with diglyme as internal standard and ee was determined by 

chiral HPLC (Chiralcel OB-H, eluent: n-hexane/ethanol, 

99:1, flow rate: 2 mL min 1 ) analysis. 

tioselectivity was observed in the shown time frame, 

while after 24 h full racemization occurred with catalyst 

A. Noteworthy, the analysis of the conversiontime 

behavior proved a higher catalyst activity for catalyst 

B, while for catalyst A a slight deceleration was 

monitored. We assume a better stabilization of the 

active species by an excess of 3a and PPh 3. 

As shown in Table 2 we also examined different 

pybox ligands (2a–c), but only unsatisfying results 

were obtained demonstrating the advantage of 3a 

(Table 2, entries 1–3). 

Noyori et al. proposed a metal-ligand bifunctional 

mechanism for the hydride transfer process (“NH effect”). 

[4,13b] Hence, the NH group of the imidazoline 

rings could be involved in the selectivity transfer and 

increase the coordination affinity between substrate 


Table 2. Transfer hydrogenation of acetophenone in the 

presence of different pybox and pybim ligands. [a] 

Entry Ligand Time [h] Conv. [%] [b] 

ee [%] [b] 

1 2a 1 6 11 (R) 

2 2b 1 10 18 (S) 

3 2c 1 22 8 (R) 

4 3a 1 83 98 (S) 

5 3b 2 95 26 (R) 

6 3c 2 74 29 (S) 

7 3d 1 4 7 (R) 

8 3e 1 77 7 (S) 

[a] Reaction conditions: 3.8 ” 10 6 mol [RuCl2ACHTUNGTRENUNG(PPh 3) 3], 1.14 ” 

10 5 mol ligand, 3.8 ” 10 6 mol PPh 3, 1.9 ”10 6 mol NaOi-Pr, 

2.0 mL isopropyl alcohol, 10 min at 100 8C then addition 

of 3.8 ” 10 4 mol acetophenone. 

[b] Conversion and ee were determined by chiral GC (50 m 

Lipodex E, 95–200 8C) analysis with diglyme as internal 

standard. 

and catalyst. Due to the formation of a second binding 

site, a more favorable position for transferring the 

chiral information is attained. [5,9,13] 

In order to understand the role of the free NH 

functionality for our pybim ligand 3a, different substitutions 

at the imidazoline units were carried out. The 

corresponding monoprotected ligands 3b, c were synthesized 

by reaction of 3a with one equivalent of 3,5di-tert-butylbenzoic 

acid chloride or Ph 2P(O)Cl. We 

presumed that the resulting unsymmetrical complexes 

would direct the substrate to occupy a specific orientation 

in the transition state and thereby induce increased 

selectivity during catalysis. However, 3,5-(t- 

Bu) 2C 6H 3)CO (3b) or Ph 2PO substitution (3c) decreased 

the enantioselectivity in the model reaction 

significantly (Table 2, entries 5 and 6). To confirm the 

results of the monosubstituted ligands an exchange of 

both hydrogens with Boc (3d) orBz(3e) protecting 

groups was carried out. A further decrease of enantioselectivity 

was observed (Table 2, entries 7 and 8). 

Thus, there is a crucial necessity of both NH functionalities 

for obtaining high enantioselectivity in the 

transfer hydrogenation of acetophenone. Interestingly, 

the NH group is not necessary to achieve significant 

conversions (Table 2, entry 8), which is in contrast to 

previous reports by Noyori et al., for example catalysts 

containing N-dimethylamino alcohols are completely 

inactive compared to their N-monomethyl 

counterparts. [3d,13b] To estimate the influence of the ligands 

in more detail we varied also the phosphorus 

ligand part (Table 3). Among the different achiral ligands 

best results were obtained with PPh 3,(p-MeO- 

C 6H 4) 3P and (p-Me-C 6H 4) 3P (Table 3, entries 1, 3 and 

Adv. Synth. Catal. 2007, 349, 853 – 860 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.asc.wiley-vch.de 855


Table 3. Influence of different phosphorus ligands on the transfer 

hydrogenation of acetophenone. [a] 

Entry P Ligand Temp. 

[8C] 

Conv. 

[%] [b] 

ee 

[%] [b] 

1 Ph 3P 100 80 94 (S) 

2 without 100 61 7 (S) 

3 (p-MeO-C 6H 4) 3P 90 91 87 (S) [c] 

4 (o-Me-C 6H 4) 3P 100 20 rac 

5 (p-Me-C 6H 4) 3P 100 41 97 (S) 

6 ACHTUNGTRENUNG[3,4-ACHTUNGTRENUNG(CF 3) 2-C 6H 3] 3P 90 24 66 (S) [c] 

7 ACHTUNGTRENUNG(p-F-C 6H 4) 3P 100 53 76 (S) 

8 Cy 3P 90 2 15 (S) [c] 

9 t-Bu 3P 100 1 12 (S) 

10 n-BuPAd 2 100 4 5 (S) 

11 ACHTUNGTRENUNG(i-PrO) 3P 100 28 75 (S) 

12 Ph 2PACHTUNGTRENUNG(CH 2)PPh 2 100 37 rac 

13 Ph 2PACHTUNGTRENUNG(CH 2) 2PPh 2 100 43 rac 

14 Ph 2PACHTUNGTRENUNG(CH 2) 5PPh 2 100 43 6 (S) 

15 Ph 2PACHTUNGTRENUNG(CH 2) 6PPh 2 100 15 37 (S) 

16 90 90 95 (S) [c] 

17 90 8 24 (S) 

[a] Reaction conditions: in situ catalyst {1.9”10 6 mol [RuCl2 

ACHTUNGTRENUNG(C 6H 6)] 2, 3.8 ” 10 6 mol 3a, 3.8 ”10 6 mol of the corresponding 

P ligand}, 1.9 ” 10 5 mol NaO-i-Pr, 2.0 mL isopropyl alcohol, 

10 min at described temperature then addition of 3.8 ” 

10 4 mol acetophenone, 1 h at described temperature. 

[b] Conversion and ee were determined by chiral GC (50 m Lipodex 

E, 95–200 8C) analysis with diglyme as internal standard. 

[c] Experiments also performed at 100 8C, but only low enantioselectivities 

or conversions were obtained. 

5). Methyl substitution in the o-position of arylphosphines 

decreased the enantioselectivity dramatically 

compared to that at the p-position (from 97 % ee to 

rac, entries 4 and 5). Moderate conversion and selectivity 

were obtained for electron-poor substituted arylphosphines 

(Table 3, entries 6 and 7). Interestingly, 

also more basic and sterically hindered alkylphosphines 

such as PCy 3,PACHTUNGTRENUNG(t-Bu) 3, and n-BuPAd 2 showed 

only low activity (Table 3, entries 8–10). 

Furthermore, we applied chelating arylphosphine ligands. 

For bis(diphenylphosphino)methane (DPPM) 

only disappointing conversion and selectivity were ob- 


tained (Table 3, entry 12). By increasing the number 

of CH 2 groups in the bridge an increase of the enantiomeric 

excess was detected (Table 3, entries 13–15), 

probably due to a weaker coordination of the second 

phosphine group to the ruthenium. In addition, to improve 

the enantioselectivity and to increase the enantiomeric 

differentiation in the shape of the catalysts, 

we investigated the influence of chiral phosphines. 

Therefore, we tested chiral monodentate ligands (S)-4 

and (S)-5 in the transfer hydrogenation of acetophenone 

in combination with pybim ligand 3a. Recently, 

we have demonstrated the successful application of 

such chiral monodentate 4,5-dihydro-3H-dinaphtho- 

[2,1-c;1’,2’-e]phosphepines in various asymmetric hydrogenations 

using molecular hydrogen. [10] Furthermore, 

Gladiali and co-workers reported previously 

the application of this ligand class in the rhodium-catalyzed 

asymmetric hydrogenation of C=C bonds. [21] 

However, only ligand (S)-4 showed comparable enantioselectivity 

to PPh 3 of 95% ee, while (S)-5 gave 

poor selectivity and conversion, due to a similar basicity 

to achiral alkylphosphines (Table 3, entry 16 and 

17). 

Next, we explored the influence of the concentration 

of PPh 3. The results indicated a necessity of 

1 equiv. of PPh 3 relating to 1 equiv. of ruthenium, 

while the reaction with more than 1 equiv. of PPh 3 or 

in the absence of PPh 3 resulted in a decrease of enantioselectivity 

(Table 3, entries 1 and 2). Noteworthy, 

the use of an excess of PPh 3 has no disordered effect 

on selectivity while a negative influence was reported 

for other catalytic systems when PPh 3 was not removed. 

[5,6] In analogy to Gimeno et al. [6,11] and Yu 

et al. [12] we assume a cis-coordination of the phosphine 

with respect to the N-N-N plane, which forms 

after removal of the cis-coordinated chlorides (with 

respect to each other) a highly selective vacancy for 

substrate coordination and chirality transfer. 

To demonstrate the usefulness of the novel catalysts 

we employed system A ([RuCl 2ACHTUNGTRENUNG(C 6H 6)] 2/pybim/PPh 3) 

and B ([RuCl 2ACHTUNGTRENUNG(PPh 3) 3]/pybim) in the asymmetric 

transfer hydrogenation of six aromatic and one aliphatic 

ketones (Table 4). In general, catalyst system 

A gave some higher enantioselectivities compared to 

catalyst B. Substituted acetophenones and propiophenone 

gave enantioselectivities up to 98% ee (Table 4, 

entries 1–5). In the case of methoxy-substitution the 

position of the substituent plays an important role, 

because ortho-substitution was favored (Table 4, entries 

3 and 4). A chloro substituent in the a-position 

to the carbonyl group proved to be problematic and 

deactivated both catalysts (Table 4, entry 6). Compared 

to aromatic ketones, aliphatic ketones are more 

challenging substrates. Nevertheless, 1-cyclohexylethanone 

was reduced by catalyst A in good yield and 

enantioselectivity (Table 4, entry 7). 



Table 4. Transfer hydrogenation of prochiral ketones. [a] 

Entry Alcohol Catalyst A [b,c,d] 

Catalyst B [b,c,d] 

Conv. [%] ee [%] Conv. [%] ee [%] 

1 89 89 (S) > 99 85 (S) 

2 84 94 (S) > 99 89 (S) 

3 86 [e] 

Various methods ( 1 H, 13 C, 31 Pand 15 N NMR, COSY 

NMR, HMQC NMR and MS) were used for characterization 

of the pre-catalyst, but unfortunately no 

precise structure has been proven. The 31 P NMR spectrum 

of the pre-catalyst in CDCl 3 indicated a single 

compound, because a singlet appeared at 30 ppm 

(free PPh 3: 6 ppm and O=PPh 3: 27 ppm). Furthermore, 

the composition of the pre-catalyst was confirmed 

by HR-MS as [RuCl 2ACHTUNGTRENUNG(PPh 3)(3a)] (calculated 

mass: 953.17549, detected mass: 953.17572). However, 

the coordination abilities of ligand 3a are so far unclear, 

because a rapid exchange of NH protons was 

detected, which causes a broad signal in the 1 HNMR 

72 (S) 68 [f] 

4 >99 98 ( ) 99 g] 

5 >99 97 (S) 98 [e] 

6 12 [g] 

70 (R) < 2 [f] 

7 91 82 (S) 96 [f] 

74 (S) 

70 ( ) 

87 (S) 

12 (R) 

[a] Reaction conditions: in situ catalyst A {1.9 ”10 6 mol [RuCl2ACHTUNGTRENUNG(C 6H 6)] 2, 3.8 ” 10 6 mol 3a, 3.8 ” 10 6 mol PPh 3), 1.9 ” 10 5 mol 

NaO-i-Pr, 2.0 mL isopropyl alcohol, 10 min at 100 8C then addition of 3.8 ” 10 4 mol substrate, 1 h at 100 8C. 

[b] Conversion and ee were determined by chiral GC (entry 1: 25 m Lipodex E, 80–180 8C; entry 2: 25 m Lipodex E, 100 8C; 

entry 3: 50 m Lipodex E, 90–105 8C; entry 4: 50 m Lipodex E, 90–180 8C; entry 5: 25 m Lipodex E, 90–1808C; entry 6: 

50 m Lipodex E, 95–180 8C; entry 7: 25 m Lipodex E, 100 8C) analysis with diglyme as internal standard. 

[c] In situ catalyst B {3.8 ”10 6 mol [RuCl2ACHTUNGTRENUNG(PPh 3) 3], 1.14 ” 10 5 mol 3a}. 

[d] The absolute configurations were determined by comparing the sign of specific rotation with reported data. 

[e] 4h. 

[f] 8h. 

[g] 24 h. 


72 (S) 

spectrum for the four protons adjacent to the nitrogen 

atoms and furthermore one signal for the corresponding 

carbons in the 13 C NMR spectrum. 

Next, we focused our attention on a deeper comprehension 

of the reaction mechanism. For metal-catalyzed 

transfer hydrogenation two general mechanisms 

are accepted, designated as direct hydrogen 

transfer via formation of a six-membered cyclic transition 

state composed of metal, hydrogen donor and acceptor, 

and the hydridic route, which is subdivided 

into two pathways, the monohydride and dihydride 

mechanism (Scheme 3). More specifically, the formation 

of monohydride-metal complexes promotes an 



exclusive hydride transfer from carbon (donor) to carbonyl 

carbon (acceptor) (Scheme 3), whereas a hydride 

transfer via dihydride-metal complexes leads to 

Scheme 3. Monohydride and dihydride mechanisms for 

transfer hydrogenations. 

no accurate prediction of hydride resting state, because 

the former hydride was transferred to the carbonyl 

carbon (acceptor) as well as to the carbonyl 

oxygen (acceptor) (Scheme 3). Indications for both 

pathways (hydridic route) have been established by 

various research groups, when following the hydride 

transfer catalyzed by metal complexes, e.g., Ru, Rh or 

Ir. [13] 

Reaction of cyclopropyl phenyl ketone (“radical 

clock”-substrate) with isopropyl alcohol in the presence 

of 1 mol % catalyst A gave exclusively the corresponding 

cyclopropylphenyl alcohol (> 99% by 

1 H NMR). Apparently there is no radical reduction 

induced by the transition metal or by sodium alkoxides. 

[14] The second assumption is also confirmed by 

performing the reduction of acetophenone in the 

presence of base and in the absence of the ruthenium 

catalyst. Here, no product at all was detected. 

Next, we followed the incorporation of hydrogen 

from the donor molecule (isopropyl alcohol) into the 

product by applying a deuterated donor. [15] The precatalyst 

(1 mol %) is generated by stirring a solution 

of isopropyl alcohol-d 8, 0.5 equivs. of [RuCl 2ACHTUNGTRENUNG(C 6H 6)] 2, 

ligand 3a and PPh 3 for 16 h at 65 8C. Then, sodium 

Scheme 4. Deuterium incorporation into acetophenone catalyzed by catalyst system A. 


isopropoxide-d 7 was added and the solution was stirred 

for 10 min at 100 8C. The reaction mixture was 

charged with acetophenone and after 1 h compound 

13 was observed as main product (> 99 %) by 

1 H NMR (Scheme 4). [16] The result proved an exclusive 

transfer of the deuterium into the carbonyl 

group, therefore a C H activation of the substrate/ 

product under the described conditions did not occur. 

Furthermore, this result rules out an enol formation 

in the catalytic cycle. [17] 

To specify the position and the nature of the transferred 

hydride, the reaction was performed with isopropyl 

alcohol-d 1 (hydroxy group deuterated) as solvent/donor 

and sodium isopropoxide as base under 

identical reaction conditions. In the transfer hydrogenation 

of acetophenone we obtained a mixture of two 

deuterated 1-phenylethanols (Scheme 4, 14a and 

14b).The ratio between 14a and 14b (85:15) indicated 

a specific migration of the hydride, albeit some scrambling 

was detected. [18] This was probably caused by rearrangement 

of the hydride complex, starting from 

HN Ru D via N=Ru(HD) to DN Ru H and subsequent 

transfer process into acetophenone yielding 

14b. In conclusion the incorporation is in agreement 

with the monohydride mechanism, implying the formation 

of a metal hydride species in the catalytic 

cycle (Scheme 3). Furthermore, this indication is confirmed 

by the above-mentioned influence of the NH 

groups. In conclusion, the transfer of hydrogen, in the 

case of catalyst A, is subdivided into the hydride 

transfer by the metal and the proton transfer by the 

NH group in analogy to the metal-ligand bifunctional 

catalysis. [13r] 

We demonstrated for the first time the successful 

application of chiral tridentate pyridinebisimidazoline 

ligands in the asymmetric ruthenium-catalyzed transfer 

hydrogenation of aliphatic and aromatic ketones. 

Enantioselectivities up to > 99% ee were obtained 

under optimized reaction conditions. Comparison experiments 

of 3a with monoprotected pybims and 

pybox ligands displayed the crucial influence of the 

free NH functionality. Mechanistic experiments indicated 

the transfer of hydrogen from the donor molecule 

into the substrate via a metal-ligand bifunctional 

mechanism. 




General Remarks 

All manipulations were performed under an argon atmosphere 

using standard Schlenk techniques. Isopropyl alcohol 

was used without further purification (purchased from 

Fluka, dried over molecular sieves). Sodium isopropoxide 

was prepared by reacting sodium with isopropyl alcohol 

under an argon atmosphere (stock solution). All ketones 

were dried over CaH 2, distilled in vacuum and stored under 

argon, except 4’-methoxyacetophenone and phenacyl chloride, 

which were used without further purification. 

BuP(Ad) 2 [19] and N-phenyl-2-(di-tert-butylphosphino)-pyrrole 

[20] were synthesized according to literature protocols. 

General Procedure for the Transfer Hydrogenation of 

Ketones 

In a 10-mL Schlenk tube, the in situ catalyst was prepared 

by stirring a solution of [RuCl 2ACHTUNGTRENUNG(C 6H 5)] 2 (1.9 ” 10 6 mmol), 

ligand 3a (3.8 ” 10 6 mmol) and PPh 3 (3.8 ” 10 6 mmol) in 

1.0 mL isopropyl alcohol for 16 h at 65 8C. To this mixture 

sodium isopropoxide (1.9 ”10 5 mmol in 0.5 mL isopropyl alcohol 

(stock solution)) was added and the solution stirred at 

100 8C for 10 min. After addition of the corresponding 

ketone (0.38 mmol in 0.5 mL isopropyl alcohol (stock solution)) 

the reaction mixture was stirred for 1 h at 100 8C. The 

solution was cooled to room temperature and filtered over a 

plug of silica. The conversion and ee were measured by GC 

without further manipulations. 


This work has been supported by the State of Mecklenburg- 

Western Pomerania and the “Bundesministerium für Bildung 

und Forschung (BMBF)”. Additional support came from the 

BMBF excellence center “CELISCA” and the “Graduiertenkolleg 

1213 - Neue Methoden für Nachhaltigkeit in Katalyse 

und Technik” and Leibniz price of the DFG. We thank Mrs. 

M. Heyken, Mrs. C. Voss, Dr. C. Fischer, Mrs. S. Buchholz 

(all Leibniz-Institut für Katalyse e.V. an der Universität Rostock) 

and J. Schumacher (Universität Rostock) for their excellent 

technical and analytical support. 

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1 

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7. Summary 

7.1. Application of monodentate phosphines in asymmetric hydrogenations 

Since previous works have proven an excellent behaviour of ligands containing 4,5–dihydro– 

3H–dinaphtho[2,1–c;1´,2´–e]phosphepine motif in asymmetric hydrogenation of α–amino 

acid precursors, itaconic acid derivatives and β–ketoesters, we extended the scope and 

limitation in the reduction of unsaturated C–C bonds. The rhodium–catalyzed asymmetric 

hydrogenation of different N–acyl enamides to give N–acyl protected optically active amines 

has been examined for the first time in detail in the presence of chiral monodentate 4,5– 

dihydro–3H–dinaphtho[2,1–c;1´,2´–e]phosphepine (Scheme 1). The enantioselectivity is 

largely dependent on the nature of the substituent at the phosphorous atom and the enamide 

structure. Under optimized conditions up to 95% ee and catalyst activity up to 2000 h -1 have 

been achieved. 

P R 

(L) 

HN 

O 

[Rh(cod) 2]BF 4 + 2.1 (L) 

H2 (2.5 bar), 


R1 R1 Scheme 1. Asymmetric hydrogenation of N–acyl enamides. 

R 2 

R 2 

HN 

O 

up to 95% ee 

Furthermore the potential of presented monophosphine ligands were shown in the rhodium– 

catalyzed asymmetric hydrogenation of various β–dehydroamino acid derivatives to give 

optically active β–amino acids (Scheme 2). Here enantioselectivities up to 94% ee were 

obtained after optimization of reaction conditions. Noteworthy, contradictory performance 

was observed for the E– and Z–isomer and different reaction conditions were necessary to 

achieve best enantioselectivity. In addition a switch of product configuration was observed 

depending on the nature of the double bond, which has been scarcely reported. 

P R 

(L) 

R 1 

O 

R 2 

NH 

O 

OR 3 

[Rh(cod) 2]BF 4 + 2.1 (L) 

H 2 

E-isomer (R)-product 

Z-isomer (S)-product 

Scheme 2. Asymmetric hydrogenation of β–dehydroamino acid derivates. 

R 1 

O 

R 2 

NH 

* 

O 

OR 3 

up to 94% ee


Based on the pioneering work of Feringa, de Vries, Minnaard and co–workers the rhodium– 

catalyzed asymmetric hydrogenation of different acyclic and cyclic enol carbamates to yield 

optically active carbamates has been studied in the presence of chiral monodentate ligands 

based on a 4,5–dihydro–3H–dinaphtho[2,1–c;1´,2´–e]phosphepine scaffold (Scheme 3). 

Various reaction parameters have been investigated in detail and enantioselectivities up to 

96% ee have been achieved with an in situ catalyst. Noteworthy, high thermal stability of the 

catalyst in the range of 10–90 °C was noticed with respect to enantioselectivity (94–96% ee). 

P R 

(L) 

N 

O O [Rh(cod) 2]BF4 + 2.1 (L) 

MeOH, 24 h, H 2 (25 bar) 

Scheme 3. Asymmetric hydrogenation of enol carbamates. 

7.2. Transfer hydrogenation 

N 

O O 

up to 96% ee 

In situ generated homogeneous iron complexes catalyze the transfer hydrogenation of 

aliphatic and aromatic ketones utilizing 2–propanol as hydrogen donor in the presence of 

base. The influence of different reaction parameters on the catalytic activity was investigated 

in detail applying a three component catalyst system, composed of an iron salt, 2,2´:6´,2´´– 

terpyridine and PPh3 (Scheme 4). The scope and limitations of the described catalyst have 

been shown in the reduction of eleven different ketones. In most cases high conversion and 

excellent chemoselectivity are achieved. Mechanistic studies indicate a monohydride reaction 

pathway for the homogeneous iron catalyst. 

O 

1/3 Fe 3(CO) 12/terpy/PPh 3 

Na-2-OPr, 2-PrOH, 100 °C, 7 h 

Scheme 4. Homogeneous iron catalyst for reduction of ketones. 

Furthermore, for the first time in situ generated iron porphyrins have been applied as 

homogeneous catalysts for the transfer hydrogenation of ketones. Using 2–propanol as 

hydrogen source various ketones are reduced to the corresponding alcohols in good to 

OH


excellent yield and selectivity. Under optimized reaction conditions high catalyst turnover 

frequencies up to 642 h -1 were achieved (Scheme 5). 

R 

N 

R 

NH N 

R 

HN 

R 

1 

O 

1/3 Fe 3(CO) 12/1 

Na-2-OPr, 2-PrOH, 100 °C, 7 h 

OH 

conversions up to >99% 

TOF up to 642 h -1 

Scheme 5. Transfer hydrogenation of ketones in the presence of biomimetic iron porphyrin 

catalysts. 

In situ generated iron porphyrins have been furthermore applied as homogeneous catalysts for 

the transfer hydrogenation of α–substituted ketones. Using 2–propanol as hydrogen donor 

various hydroxyl-protected 1,2–hydroxyketones are reduced to the corresponding mono 

protected 1,2–diols in good to excellent yield. Under optimized reaction conditions catalyst 

turnover frequencies up to 2500 h -1 have been achieved (Scheme 6). 

R 

NH N 

N 

R 

R 

HN 

R 

1 

R 1 

O 

R 2 

OR 3 

FeCl 2/1 

NaOH, 2-PrOH, 100 °C 

R 1 

OH 

R 2 

OR 3 

conversions up to >99% 


Scheme 6. Transfer hydrogenation of α–substituted ketones in the presence of biomimetic 

iron porphyrin catalysts. 

Novel ruthenium carbene complexes have been in situ generated and tested for the transfer 

hydrogenation of ketones. Applying Ru(cod)(methylallyl)2 in the presence of imidazolium 

salts in 2–propanol and sodium–2–propanolate as base, turnover frequencies up to 346 h -1 

have been obtained for the reduction of acetophenone (Scheme 7). A comparative study 

involving ruthenium carbene and ruthenium phosphine complexes demonstrated higher 

activity of ruthenium carbene complexes.

L = 

Cl - 

N + 

N 


O OH 

[Ru(cod)methylallyl2]/L Na-2-OPr, 2-PrOH, 100 °C 

conversion up to >99% 


Scheme 7. Transfer hydrogenation of ketones in the presence of ruthenium carbene catalysts. 

Tridentate N,N,N–pyridinebisimidazolines have been studied as new ligands for the 

enantioselective transfer hydrogenation of prochiral ketones. High yield and excellent 

enantioselectivity up to >99% ee have been achieved with an in situ generated catalytic 

system containing dichlorotris(triphenylphosphine)ruthenium and 2,6–bis–([4R,5R]–4,5– 

diphenyl–4,5–dihydro–1H–imidazol–2–yl)–pyridine in the presence of sodium 2–propanolate 

(Scheme 8). 

L = 

H H 

Ph 

N 

N 

N 

Ph 

N N 

Ph 

Ph 

O 

[RuCl 2(PPh 3) 3]/3L 

Na-2-OPr, 2-PrOH, 100 °C, 1 h 

OH 

* 

up to >99% ee 

Scheme 8. New ruthenium catalysts for asymmetric transfer hydrogenation of prochiral 

ketones.

Abstract 

Abstract 

Die vorliegende Dissertation beschäftigte sich mit der Anwendung von monodentaten 

Phosphinliganden in der asymmetrischen Hydrierung von C–C Doppelbindungen. Dabei 

konnte die Wirksamkeit von Rhodiumkatalysatoren, die Phosphinliganden mit der 4,5– 

Dihydro–3H–dinaphtho[2,1–c;1´,2´–e]phosphepin–Struktureinheit enthielten, gezeigt werden. 

Verschiedenste prochirale Substratklassen, wurden mit exzellenten Enantioselektivitäten von 

bis zu 96% ee zu den entsprechenden ungesättigten Derivaten reduziert. Ein zweiter 

Schwerpunkt der Arbeit lag in der Entwicklung neuartiger eisenbasierter Hydrierkatalysatoren 

und deren Anwendung in der Transferhydrierung von Ketonen, wobei Katalysatoraktivitäten 

von bis zu 2500 h -1 (TOF) erzielt werden konnten. 

This dissertation deals with the application of monodentate phosphine ligands in asymmetric 

hydrogenation of C–C double bonds. The usefulness of rhodium catalysts containing 

phosphines based on the 4,5–Dihydro–3H–dinaphtho[2,1–c;1´,2´–e]phosphepine scaffold was 

demonstrated in the reduction of various prochiral substrates, since excellent 

enantioselectivities up to 96% ee were achieved. Furthermore, the properties of iron–based 

catalysts were studied in the field of transfer hydrogenation. Here high catalyst activities up to 

2500 h -1 were obtained in the reduction of ketones.

PERSONAL INFORMATION 

Surname: Enthaler 

First name: Stephan 

Curriculum Vitae 


Current adress: Thomas-Müntzer-Platz 21 

Nationality: German 

Birthday: 27.02.1980 

18057 Rostock (Germany) 

Birthplace: Hagenow (Germany) 

EDUCATION 

1986 – 1990 Elementary school “Ludwig-Reinhard-Schule“ in Boizenburg/Elbe 

1990 – 1992 August-Bebel-Schule in Boizenburg/Elbe 

1992 – 1998 Gymnasium Boizenburg 

1998 Abitur (degree: General qualification for university entrance) 

1999 – 2004 Course of studies: Chemistry at the University of Rostock (Diplom-Chemie) 

2003 – 2004 Master thesis (Diplomarbeit): “Synthesis and application of novel monodentate 

phosphine ligands in asymmetric hydrogenations“ under the supervision of 

Prof. M. Beller 

2004 Degree: Diplom-Chemiker (Master of Science) 

since 2004 PhD thesis at the University of Rostock under the supervision of Prof. M. 

Beller 

RESEARCH EXPERIENCE 

2001 Student assistant in the group of Prof. R. Mietchen at the University of 

Rostock: “Phase transfer catalysis assisted by ultrasound“

TEACHING EXPERIENCE 


2002 Student assistant at the University of Rostock: “Practical course for medical 

students“ 

RELATED PROFESSIONAL EXPERIENCE 

2002 Student assistant at the University of Rostock: “IUPAC Conference on 

Chemical Thermodynamics (ICCT-2002)” 

DEPARTMENTAL ACTIVITIES 

2000 – 2003 Representative of the chemistry student council at the University of Rostock 

PROFESSIONAL ASSOCIATIONS 

GDCh (Gesellschaft Deutscher Chemiker) 

MILITARY SERVICE 

1998 – 1999 Basic military service: 3./183 and 1./183 armoured battalion in Boostedt

PUBLICATIONS 

JOURNAL CONTRIBUTIONS 

1. “Synthesis of chiral monodentate binaphthophosphepine ligands and their application 

in asymmetric hydrogenation“ K. Junge, B. Hagemann, S. Enthaler, A. Spannenberg, 

M. Michalik, G. Oehme, A. Monsees, T. Riermeier, M. Beller, Tetrahedron: 

Asymmetry 2004, 15, 2621–2631. 

2. “Enantioselective hydrogenation of β–ketoesters with monodentate ligands” K. Junge, 

B. Hagemann, S. Enthaler, G. Oehme, M. Michalik, A. Monsees, T. Riermeier, U. 

Dingerdissen, M. Beller, Angew. Chem. Int. Ed. 2004, 43, 6150; Angew. Chem. 2004, 

116, 5176–5179; Angew. Chem. Int. Ed. 2004, 43, 5066–5069. 

3. “A general method fort the enantioselective hydrogenation of β–ketoesters using 

monodentate binaphthophosphepine ligands“ B. Hagemann, K. Junge, S. Enthaler, M. 

Michalik, T. Riermeier, A. Monsees, M. Beller, Adv. Synth. Catal. 2005, 1978–1986. 

4. “Enantioselective rhodium–catalyzed hydrogenation of enamides in the presence of 

chiral monodentate phosphanes” S. Enthaler, B. Hagemann, G. Erre, K. Junge, M. 

Beller, Eur. J. Org. Chem. 2006, 2912–2917. 

5. “An environmentally benign process for the hydrogenation of ketones with 

homogeneous iron catalysts” S. Enthaler, B. Hagemann, G. Erre, K. Junge, M. Beller 

Chem. Asian. J. 2006, 1, 598–604. 

6. “Biomimetic transfer hydrogenation of ketones with iron porphyrin catalysts” S. 

Enthaler, G. Erre, M. K. Tse, K. Junge, M. Beller, Tetrahedron Lett. 2006, 47, 8095– 

8099. 

7. “Efficient transfer hydrogenation of ketones in the presence of ruthenium Nheterocyclic 

carbene catalysts” S. Enthaler, R. Jackstell, B. Hagemann, K. Junge, G. 

Erre, M. Beller, J. Organomet. Chem. 2006, 691, 4652–4659. 

8. “Synthesis and catalytic application of novel binaphthyl–derived phosphorous 

ligands” K. Junge, B. Hagemann, S. Enthaler, G. Erre, M. Beller, ARKIVOC, 2007, 5, 

50–66. 

9. “Development of practical rhodium phosphine catalysts for the hydrogenation of β– 

dehydroamino acid derivates” S. Enthaler, G. Erre, K. Junge, J. Holz, A. Börner, E. 

Alberico, I. Nieddu, S. Gladiali, M. Beller, Org. Process Res. Dev. 2007, 11, 568–577. 

10. “New ruthenium catalysts for asymmetric transfer hydrogenation of ketones” S. 

Enthaler, B. Hagemann, S. Bhor, G. Anilkumar, M. K. Tse, B. Bitterlich, K. Junge, G. 

Erre, M. Beller Adv. Synth. Catal. 2007, 349, 853–860.

11. “Enantioselective rhodium-catalyzed hydrogenation of enol carbamates in the 

presence of monodentate phosphines” S. Enthaler, G. Erre, K. Junge, D. Michalik, A. 

Spannenberg, S. Gladiali, M. Beller, Tetrahedron: Asymmetry, 2007, 18, 1288–1298. 

12. “Novel rhodium catalyst for asymmetric hydroformylation of styrene: Study of 

electronic and steric effects of phosphorus seven–membered ring ligands” G. Erre, S. 

Enthaler, K. Junge, S. Gladiali, M. Beller, J. Mol. Catal. A, 2008, 280, 148–155. 

13. “Synthesis and application of chiral monodentate phosphines in asymmetric 

hydrogenation” G. Erre, S. Enthaler, K. Junge, S. Gladiali, M. Beller, Coord. Chem. 

Rev. 2008, in print. 

14. “2–Hydroxy– and 2–amino–functional arylphosphines – syntheses, reactivity and use 

in catalysis” J. Heinicke, W. Wawrzyniak, N. Peulecke, B. R. Aluri, M. K. 

Kindermann, P. G. Jones, S. Enthaler, M. Beller, Phosphorus, Sulfur, Silicon and Rel. 

Elements, 2008, in print. 

15. “Synthesis of 1,2-diols via biomimetic transfer hydrogenation with iron porphyrin 

catalysts” S. Enthaler, B. Spilker, G. Erre, M. K. Tse, K. Junge, M. Beller, 

Tetrahedron, in print. 

16. “Iron–catalyzed Enantioselective Hydrosilylation of Ketones��” 

N. S. Shaikh, S. 

Enthaler, K. Junge, M. Beller, Angew. Chem. 2008, accepted. 

17. “Sustainable metal catalysis with iron – from rust to a rising star?” S. Enthaler, K. 

Junge, M. Beller, Angew. Chem. 2008, accepted. 

18. “Synthesis of new monodentate phosphoramidites and their application in iridiumcatalyzed 

asymmetric hydrogenations” G. Erre, K. Junge, S. Enthaler, D. Addis, D. 

Michalik, A. Spannenberg, M. Beller, Chem. Asian J. 2008, submitted. 

POSTER CONTRIBUTIONS 

1. “First enantioselective hydrogenation of β–ketoesters using monodentate ligands“ K. 

Junge, B. Hagemann, S. Enthaler, M. Beller, A. Monsees, T. Riermeier, ORCHEM, 

Bad Nauheim (Germany), 9–11 September 2004. 

2. “Enantioselective hydrogenation of β–ketoesters using monodentate ligands“ S. 

Enthaler, K. Junge, B. Hagemann, A. Monsees, T. Riermeier, M. Beller, COST-D24 

STEREOCAT2004, Venedig (Italy), 16–19 September 2004. 

3. “Enantioselective hydrogenation of β−ketoesters using monodentate phosphepine 

ligands“ B. Hagemann, K. Junge, S. Enthaler, A. Monsees, T. Riermeier, M. Beller, 8. 

SFB Symposium FB 380, FZ-Jülich (Germany), 7–8 Oktober 2004. 

4. “Application of monodentate binaphthophosphepine ligands in asymmetric 

hydrogenations“ S. Enthaler, K. Junge, B. Hagemann, A. Monsees, T. Riermeier, M.

Beller, XXXVIII. Jahrestreffen Deutscher Katalytiker, Weimar (Germany), 16–18 

March 2005. 

5. “Application of monodentate binaphthophosphepine ligands in asymmetric 

hydrogenations“ S. Enthaler, K. Junge, B. Hagemann, A. Monsees, T. Riermeier, M. 

Beller, Green Chemistry: Development of Sustainable Processes, Rostock (Germany), 

30 March – 1 April 2005. 

6. “First enantioselective hydrogenation of β–ketoesters using monodentate ligands” K. 

Junge, S. Enthaler, B. Hagemann, A. Monsees, T. Riermeier, M. Beller, Green 

Chemistry: Development of Sustainable Processes, Rostock (Germany), 30 March – 1 

April 2005. 

7. “Synthesis of monodentate binaphthophosphepine ligands and their application in 

asymmetric hydrogenation” B. Hagemann, K. Junge, S. Enthaler, G. Erre, A. 

Monsees, T. Riermeier, M. Beller, The 2005 European Younger Chemists´ 

Conference, Brno (Czech Republic), 31 August – 3 September 2005. 

8. “Novel axially–chiral monodentate P–donor ligands for asymmetric catalysis“ G. Erre, 

K. Junge, S. Enthaler, B. Hagemann, F. Marras, S. Gladiali, M. Beller, XXXIX. 

Jahrestreffen Deutscher Katalytiker, Weimar (Germany), 15–17 March 2006. 

9. “Novel axially–chiral monodentate P–donor ligands for asymmetric catalysis“ G. Erre, 

K. Junge, S. Enthaler, B. Hagemann, F. Marras, S. Gladiali, M. Beller, XXII 

International Conference on Organometallic Chemistry (ICOMC 2006), Zaragoza 

(Spain), 23–28 July 2006. 

10. “Enantioselective rhodium–catalyzed hydrogenation of enamides in the presence of 

chiral monodentate phosphines“ S. Enthaler, B. Hagemann, K. Junge, G. Erre, M. 

Beller, Bayer–Doktorandenkurs, Leverkusen–Monheim–Wuppertal (Germany), 20–25 

August 2006. 

11. “Enantioselective hydrogenation of enamides and enol carbamates with monodentate 

binaphthophosphepines” S. Enthaler, G. Erre, K. Junge, M. Beller, 1 st European 

Chemistry Congress (1 st ECC), Budapest (Hungary), 26 August – 01 September 2006. 

12. “Synthesis of chiral binaphthophosphepine ligands and their application in asymmetric 

catalysis” G. Erre, K. Junge, B. Hagemann, S. Enthaler, M. Beller, 4 th International 

Forum Life Science Automation, Rostock (Germany), 14–15 September 2006. 

13. “Synthesis and catalytic applications of novel binaphthyl–derived phosphorous 

ligands” K. Junge, G. Erre, S. Enthaler, M. Beller, 40. Jahrestreffen Deutscher 

Katalytiker, Weimar (Germany), 14–16 March 2007. 

14. “Rhodium phosphine catalysts for the hydrogenation of β–dehydroamino acid 

derivates” S. Enthaler, G. Erre, K. Junge, J. Holz, A. Börner, E. Alberico, I. Nieddu, S. 

Gladiali, M. Beller, Heidelberg Forum of Molecular Catalysis, Heidelberg (Germany), 

22 June 2007.

15. “Asymmetric hydrogenation of enamides – from benchmark substrates to indol 

alkaloids” S. Enthaler, G. Erre, K. Junge, M. Beller, 15 th European Symposium on 

Organic Chemistry, Dublin (Ireland), 8–13 July, 2007. 

16. “Rhodium phosphine catalysts for the hydrogenation of β–dehydroamino acid 

derivates” S. Enthaler, G. Erre, K. Junge, J. Holz, A. Börner, E. Alberico, I. Nieddu, S. 

Gladiali, M. Beller, 10 th JCF–Frühjahrssymposium, Rostock (Germany), 27–29 

March 2008. 

17. “New phosphine–Ligands for palladium–catalyzed coupling reactions” T. Schulz, S. 

Enthaler, C. Torborg, T. Schareina, A. Zapf, M. Beller, 10 th JCF– 

Frühjahrssymposium, Rostock (Germany), 27–29 March 2008. 

PATENTS 

1. “Chirale Eisen–Phosphan–Katalysatoren und deren Verwendung in selektiven 

Hydrierungsreaktionen“ S. Enthaler, K. Junge, M. Beller, DE, submitted. 

2. „Chirale Eisen–Katalysatoren mit stickstoffhaltigen Liganden und deren Verwendung 

in selektiven Hydrierungsreaktionen“ S. Enthaler, K. Junge, M. Beller, DE, submitted. 

BOOK CONTRIBUTIONS 

“Applications of iron catalysts in reduction chemistry” S. Enthaler, K. Junge, M. Beller in 

B. Plietker (Ed.) “Iron catalysis in organic chemistry“ Wiley–VCH, Weinheim, 2008. 

TALKS 

1. “Development of new monodentate phosphine ligands for asymmetric hydrogenation” 

S. Enthaler, COST–D24 STEREOCAT2005, Barcelona (Spain), 15–18 September 

2005. 

2. “Development of new monodentate phosphine ligands for asymmetric hydrogenation” 

S. Enthaler, BASF–IfOK–Symposium, Ludwigshafen (Germany), 14–16 November 

2005.

Eidesstattliche Erklärung 

Ich versichere hiermit an Eides statt, dass ich die vorliegende Arbeit selbstständig angefertigt 

und ohne fremde Hilfe verfasst habe, keine außer den von mir angegebenen Hilfsmitteln und 

Quellen dazu verwendet habe und die den benutzten Werken inhaltlich und wörtlich 

entnommenen Stellen als solche kenntlich gemacht habe. 

Rostock, den 04.05.2007

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